Methods for preparing bis-tetrahydroisoquinoline-containing compounds

ABSTRACT

(−)-Jorumycin, ecteinascidin 743, saframycin A and related compounds, methods of preparing the same, formulations comprising the compounds, and methods of treating proliferative diseases with the same are provided.

RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.16/038,968 filed Jul. 18, 2018, which claims the benefit of U.S.Provisional Application No. 62/534,493, filed Jul. 19, 2017, the entirecontents of which are incorporated herein by reference.

GOVERNMENT SUPPORT

This invention was made with government support under Grants Nos.GM080269 and GM127972 awarded by the National Institutes of Health andGrant No. CHE1205646 awarded by the National Science Foundation. Thegovernment has certain rights in the invention.

BACKGROUND

The bis-tetrahydroisoquinoline (bis-THIQ) family of natural products hasbeen studied intensively in the 40 years since their initial discovery.This family of molecules is highlighted by exceptionally potentanticancer activity in addition to strong gram-positive andgram-negative antibiotic character. Jorumycin is considered the minimumpharmacophore of this natural product family, possessing a pentacycliccore, polyoxygenated termini, and carbinolamine functionality that lendthese natural products their marked biological activity. To date,existing synthetic strategies toward the bis-THIQ natural products haverelied heavily on electrophilic aromatic chemistry, such as thePictet-Spengler reaction, which has limited the synthesis of non-naturalanalogs to highly electron-rich species that facilitate this reactivity.Accordingly, there is a need to devlop new routes to access jorumycinand related analogs in the bis-THIQ family of natural products whichhave a full range of electrophilicity in substituents on the pentacycliccore, including electron deficient analogs.

SUMMARY

The present disclosure relates in part to the synthesis of jorumycin andstructurally-related compounds, e.g., using a concise and convergentcross-coupling/enantioselective isoquinoline hydrogenation strategy,providing bis-THIQ compounds, including electron-deficient bis-THIQvariants.

Accordingly, in some embodiments, the present disclosure provides amethod for preparing a compound of Formula (I):

comprising contacting a compound of Formula (II):

-   with a transition metal catalyst (preferably a chiral transition    metal catalyst) under hydrogenation conditions, wherein, as valence    and stability permit:-   R¹ and R⁷ are each independently hydrogen, hydroxyl, halogen, nitro,    alkyl, alkenyl, alkynyl, cyano, carboxyl, sulfate, amino, alkoxy,    alkylamino, alkylthio, ether, thioether, ester, amide, thioester,    carbonate, carbamate, urea, sulfonate, sulfone, sulfoxide,    sulfonamide, acyl, acyloxy, trialkylsilyloxy, or acylamino;-   each instance of R², R³, R⁴, R⁵, R⁸, R⁹, R¹⁰, and R¹¹ is    independently hydrogen, hydroxyl, halogen, nitro, alkyl, alkenyl,    alkynyl, cyano, carboxyl, sulfate, amino, alkoxy, alkylamino,    alkylthio, ether, thioether, ester, amide, thioester, carbonate,    carbamate, urea, sulfonate, sulfone, sulfoxide, sulfonamide, acyl,    acyloxy, trialkylsilyloxy, acylamino, aryl, heteroaryl, carbocyclyl,    heterocyclyl aralkyl, aralkyloxy, hetaralkyl, carbocyclylalkyl, or    heterocyclylalkyl;-   R⁶ is hydrogen, hydroxyl, halogen, nitro, cyano, carboxyl, sulfate,    alkyl, alkenyl, alkynyl, amino, alkoxy, alkylamino, alkylthio,    ether, thioether, ester, amide, thioester, carbonate, carbamate,    urea, sulfonate, sulfone, sulfoxide, sulfonamide, acyl, acyloxy,    trialkylsilyloxy, or acylamino; or-   any two of R¹, R², R³, R⁴, R⁵, and R⁶, together with the carbon    atoms to which they are attached, form an aryl, heteroaryl,    carbocyclyl, or heterocyclyl; or-   any two of R⁷, R⁸, R⁹, R¹⁰, and R¹¹, together with the carbon atoms    to which they are attached, form an aryl, heteroaryl, carbocyclyl,    or heterocyclyl; and R¹² is H, alkyl or aralkyl.

In other embodiments, the present disclosure provides a method ofpreparing a compound of Formula (II):

comprising combining a compound of Formula (III):

a compound of Formula (IV):

and

-   a transition metal catalyst under cross-coupling conditions,    wherein, as valence and stability permit:-   R¹ and R⁷ are each independently hydrogen, hydroxyl, halogen, nitro,    alkyl, alkenyl, alkynyl, cyano, carboxyl, sulfate, amino, alkoxy,    alkylamino, alkylthio, ether, thioether, ester, amide, thioester,    carbonate, carbamate, urea, sulfonate, sulfone, sulfoxide,    sulfonamide, acyl, acyloxy, alkylsilyloxy, or acylamino;-   each instance of R², R³, R⁴, R⁵, R⁸, R⁹, R¹⁰, and R¹¹ is    independently hydrogen, hydroxyl, halogen, nitro, alkyl, alkenyl,    alkynyl, cyano, carboxyl, sulfate, amino, alkoxy, alkylamino,    alkylthio, ether, thioether, ester, amide, thioester, carbonate,    carbamate, urea, sulfonate, sulfone, sulfoxide, sulfonamide, acyl,    acyloxy, alkylsilyloxy, acylamino, aryl, heteroaryl, carbocyclyl, or    heterocyclyl;-   R⁶ is hydrogen, hydroxyl, halogen, nitro, alkyl, alkenyl, alkynyl,    cyano, carboxyl, sulfate, amino, alkoxy, alkylamino, alkylthio,    ether, thioether, ester, amide, thioester, carbonate, carbamate,    urea, sulfonate, sulfone, sulfoxide, sulfonamide, acyl, acyloxy,    alkylsilyloxy, or acylamino; or-   any two of R¹, R², R³, R⁴, R⁵, and R⁶, together with the carbon    atoms to which they are attached, form an aryl, heteroaryl,    carbocyclyl, or heterocyclyl; or-   any two of R⁷, R⁸, R⁹, R¹⁰, and R¹¹, together with the carbon atoms    to which they are attached, form an aryl, heteroaryl, carbocyclyl,    or heterocyclyl; and-   R¹³ and R¹⁴ are each independently hydroxyl, nitro, cyano, carboxyl,    sulfate, amino, alkoxy, alkylamino, alkylthio, ether, thioether,    ester, amide, thioester, carbonate, carbamate, urea, sulfonate,    sulfone, sulfoxide, sulfonamide, acyl, acyloxy, alkylsilyloxy, or    acylamino.

In other embodiments, the present disclosure provides a method ofpreparing a compound of Formula (VIII):

comprising contacting a compound of Formula (VII):

-   with a transition metal catalyst under hydrogenation conditions,    wherein, as valence and stability permit:-   R⁶ and R¹⁶ are each independently hydrogen, hydroxyl, halogen,    nitro, alkyl, alkenyl, alkynyl, cyano, carboxyl, sulfate, amino,    alkoxy, alkylamino, alkylthio, ether, thioether, ester, amide,    thioester, carbonate, carbamate, urea, sulfonate, sulfone,    sulfoxide, sulfonamide, acyl, acyloxy, alkylsilyloxy, or acylamino;-   each instance of R¹, R², R³, R⁴, and R⁵ is independently hydrogen,    hydroxyl, halogen, nitro, alkyl, alkenyl, alkynyl, cyano, carboxyl,    sulfate, amino, alkoxy, alkylamino, alkylthio, ether, thioether,    ester, amide, thioester, carbonate, carbamate, urea, sulfonate,    sulfone, sulfoxide, sulfonamide, acyl, acyloxy, trialkylsilyloxy,    acylamino, aryl, heteroaryl, carbocyclyl, or heterocyclyl; or-   any two of R², R³, R⁴, and R⁵, together with the carbon atoms to    which they are attached, form an aryl, heteroaryl, carbocyclyl, or    heterocyclyl.

In other embodiments, the present disclosure provides a compound ofFormula (V):

wherein:

-   R¹ and Rare each independently hydrogen, carbonyl, thiocarbonyl,    imine, oxime, hydroxyl, halogen, nitro, alkyl, alkenyl, alkynyl,    cyano, carboxyl, sulfate, amino, alkoxy, alkylamino, alkylthio,    ether, thioether, ester, amide, thioester, carbonate, carbamate,    urea, sulfonate, sulfone, sulfoxide, sulfonamide, acyl, acyloxy,    alkylsilyloxy, or acylamino;-   each instance of R², R³, R⁴, and R⁵ is independently hydrogen,    carbonyl, thiocarbonyl, imine, oxime, hydroxyl, halogen, nitro,    alkyl, alkenyl, alkynyl, cyano, carboxyl, sulfate, amino, alkoxy,    alkylamino, alkylthio, ether, thioether, ester, amide, thioester,    carbonate, carbamate, urea, sulfonate, sulfone, sulfoxide,    sulfonamide, acyl, acyloxy, alkylsilyloxy, acylamino, aryl,    heteroaryl, carbocyclyl, or heterocyclyl;-   each instance of R⁸, R⁹, R¹⁰, and R¹¹ is independently hydrogen,    carbonyl, thiocarbonyl, hydroxyl, halogen, nitro, alkyl, alkenyl,    alkynyl, cyano, carboxyl, sulfate, amino, alkoxy, alkylamino,    alkylthio, ether, thioether, ester, amide, thioester, carbonate,    carbamate, urea, sulfonate, sulfone, sulfoxide, sulfonamide, acyl,    acyloxy, alkylsilyloxy, acylamino, aryl, heteroaryl, carbocyclyl, or    heterocyclyl;-   R⁶ is hydrogen, hydroxyl, halogen, nitro, alkyl, alkenyl, alkynyl,    cyano, carboxyl, sulfate, amino, alkoxy, alkylamino, alkylthio,    ether, thioether, ester, amide, thioester, carbonate, carbamate,    urea, sulfonate, sulfone, sulfoxide, sulfonamide, acyl, acyloxy,    alkylsilyloxy, or acylamino; or-   any two of R¹, R², R³, R⁴, R⁵, and R⁶, together with the carbon    atoms to which they are attached, form an aryl, heteroaryl,    carbocyclyl, or heterocyclyl; or-   any two of R⁷, R⁸, R⁹, R¹⁰, and R¹¹, together with the carbon atoms    to which they are attached, form an aryl, heteroaryl, carbocyclyl,    or heterocyclyl;-   R⁵ is hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, carboxyl,    sulfate, amino, alkoxy, alkylamino, alkylthio, sulfonate, sulfone,    sulfoxide, acyl, acylamino, aryl, heteroaryl, carbocyclyl,    heterocyclyl, aralkyl, aralkyloxy, hetaralkyl, carbocyclylalkyl, or    heterocyclylalkyl; and-   X is hydrogen, oxo (═O), ═S, ═NH, ═N-alkyl, ═NOH, hydroxyl, halogen,    nitro, alkyl, alkenyl, alkynyl, cyano, carboxyl, sulfate, amino,    alkoxy, alkylamino, alkylthio, ether, thioether, ester, amide,    thioester, carbonate, carbamate, urea, sulfonate, sulfone,    sulfoxide, sulfonamide, acyl, acyloxy, alkylsilyloxy, acylamino,    aryl, heteroaryl, carbocyclyl, heterocyclyl, aralkyl, aralkyloxy,    hetaralkyl, carbocyclylalkyl, or heterocyclylalkyl; or a    pharmaceutically acceptable salt thereof.

In certain embodiments, the present disclosure provides pharmaceuticalcompositions comprising a compound of formula V, VA, VB, VI, VIA, orVIB, or a pharmaceutically acceptable salt thereof. In certainembodiments, the present disclosure provides a method of treating aproliferative disorder, comprising administering to a patient in needthereof a therapeutic amount of a compound of formula V, VA, VB, VI,VIA, or VIB, or a pharmaceutically acceptable salt thereof. These, andother embodiments, will be described in more detail herein.

DETAILED DESCRIPTION

As significantly as knowledge of cancer biology has grown over the pasthalf-century, so too has reliance on natural products as a major sourceof inspiration for the development of novel chemotherapeutic agents.Indeed, more than 60% of anticancer agents developed between 1981-2014were either natural products themselves or were derived from a naturalproduct.¹

One set of molecules that has contributed to this endeavor is thebis-tetrahydroisoquinoline (bis-THIQ) family of natural products,featuring jorumycin (1), ecteinascidin 743 (Et 743, 2), and saframycin A(3).²⁻⁴ For example, Et 743 (Yondelis®, trabectidin) has been approvedin the US, Europe, and elsewhere for the treatment of a variety of drugresistant and unresectable soft-tissue sarcomas and ovarian cancer.Although 2 is available from nature, isolation of one gram of materialwould require in excess of one ton of biological material.⁵ For thisreason, the successful application of 2 as an anti-tumor agent hasnecessitated its large-scale chemical synthesis, a daunting task for amolecule of such immense complexity.⁶

Due to their unique chemical structures, exceedingly potent biologicalactivity, and unique mechanism of action²⁻⁴ the bis-THIQ naturalproducts have been studied intensively by chemists and biologists alikeduring the 40+ years since their initial discovery. From a syntheticstandpoint, Corey and coworkers' synthesis of Et 743⁷ and Myers andcoworkers' synthesis of saframycin A⁸ are considered landmark synthesesdue to their brevity, efficiency, and creative applications of bothnovel and traditional chemical technology. In particular, thesesyntheses relied on classical electrophilic aromatic substitution (EAS)chemistry, such as the Pictet-Spengler and Bischler-Napieralskireactions, for the construction of the THIQ motifs in their respectivenatural products. Recent studies on the biosynthesis of compounds 2 and3 have found that a number of non-ribosomal peptide synthetases performnearly identical transformations in nature; these enzymes are referredto as Pictet-Spenglerases as a result.^(9,10)

The highly oxygenated aromatic termini of the pentacyclic bis-THIQ corehas led to a strong reliance on EAS-based strategies for theconstruction of the requisite THIQ subunits found in the naturalproducts. Such approaches have allowed for the successful development ofnon-natural bis-THIQ analogs that possess similar levels of potency tothe natural products but with greatly simplified molecular structures,most notably a quinaldic acid derivative (5)¹¹, phthalascidin650^(12,13), and PM-00104/50 (Zalypsis®).¹⁴

Et 743 QAD IC₅₀ (A375 0.15 nM 1.3 nM melanoma) IC₅₀ (A549  1.0 nM 4.4 nMlung cancer) t_(1/2) (rodent)   20 hr  17 min t_(1/2) (human) 96-180 hr(NA) EAS chemistry precludes the synthesis of electron deficient analogs

Since its isolation in 2000,¹⁵ jorumycin been the target of a number ofsynthetic endeavors, including four total syntheses¹⁶⁻¹⁹ and twosemi-syntheses.^(20,21) Similar to the strategies discussed above,EAS-based reactions have been heavily utilized in these studies.Jorumycin possesses all of the defining features of the bis-THIQ naturalproducts—the penta-cyclic carbon skeleton, the polyoxygenated ringtermini, and the central carbinolamine—that together provide the markedbio-logical activity of this natural product family.²² Furthermore, theoxygen substitution appended to the B-ring (4, X═OH) is an excellentstarting point for the diversification of jorumycin to theecteinascidin, saframycin, and renieramycin scaffolds.²⁻⁴ Jorumycinexhibits an IC₅₀ of 0.24 nM vs. A549 lung cancer, 0.49 nM vs. DU145prostate cancer, and 0.57 nM vs. HCT116 colon cancer,^(15,19,20) thusoffering immense therapeutic potential.

In selecting jorumycin as a target of synthetic endeavors,derivatization studies were considered.¹¹⁻¹⁴ While these studies havesucceeded in producing analogs with similar potency, none hassuccessfully navigated clinical trials to achieve approval for use inhumans, whether in the US or elsewhere. One potential reason for this isa significant difference in metabolic stability. For instance, Et 743,which is a currently marketed drug, has an in vivo half-life (t_(1/2))of 96-180 hours in humans and 20 hours in rodents.^(23,24) In contrast,quinaldic acid saframycin A derivative 5 has a rodent in vivo half-lifeof just 17 minutes.²⁵

It has been shown through interaction with both human and mouse livermicrosomes that the bis-THIQ natural products undergo oxidation bycytochrome P450 isoform 3A4, resulting in oxidative molecularbifurcation.²⁶ It is important to note that although jorumycin andsaframycin A possess quinone rings, these portions of the naturalproducts are rapidly reduced in vivo through a glutathione- orNADPH-mediated pathway, resulting in the fully aromatic and veryelectron-rich hydroquinone forms.²²

In view of this information, it was posited that an ideal researchprogram directed at synthesizing new bis-THIQ analogs should aim to (1)improve or maintain potency, (2) simplify the structure of the activepharmaceutical ingredient, and (3) extend metabolic stability.

Typically, extending a drug candidate's half-life involves blockingenzymatic oxidation of the compound through the synthesis ofelectron-deficient analogs. For this reason, the present syntheticmethodology is dissonant with conventional methods for the constructionof the bis-THIQ natural products, since preparing electron-deficientanalogs would be very challenging if one were to utilize a synthesisbuilt upon EAS-based strategies. These approaches fundamentally rely onthe special reactivity of electron-rich, it-nucleophilic aromatic rings,and electron-withdrawing groups tend to fully deactivate this type ofchemistry. Thus, the present inventors set out to develop an orthogonalsynthesis aimed at allowing access to this class of electron-deficientbis-THIQ analogs.

Compounds

In some embodiments, the present disclosure provides a method forpreparing a compound of Formula (I):

comprising contacting a compound of Formula (II):

-   with a transition metal catalyst (preferably a chiral transition    metal catalyst) under hydrogenation conditions, wherein, as valence    and stability permit:-   R¹ and R⁷ are each independently hydrogen, hydroxyl, halogen, nitro,    alkyl, alkenyl, alkynyl, cyano, carboxyl, sulfate, amino, alkoxy,    alkylamino, alkylthio, ether, thioether, ester, amide, thioester,    carbonate, carbamate, urea, sulfonate, sulfone, sulfoxide,    sulfonamide, acyl, acyloxy, trialkylsilyloxy, or acylamino;-   each instance of R², R³, R⁴, R⁵, R⁸, R⁹, R¹⁰, and R¹¹ is    independently hydrogen, hydroxyl, halogen, nitro, alkyl, alkenyl,    alkynyl, cyano, carboxyl, sulfate, amino, alkoxy, alkylamino,    alkylthio, ether, thioether, ester, amide, thioester, carbonate,    carbamate, urea, sulfonate, sulfone, sulfoxide, sulfonamide, acyl,    acyloxy, trialkylsilyloxy, acylamino, aryl, heteroaryl, carbocyclyl,    heterocyclyl aralkyl, aralkyloxy, hetaralkyl, carbocyclylalkyl, or    heterocyclylalkyl;-   R⁶ is hydrogen, hydroxyl, halogen, nitro, cyano, carboxyl, sulfate,    alkyl, alkenyl, alkynyl, amino, alkoxy, alkylamino, alkylthio,    ether, thioether, ester, amide, thioester, carbonate, carbamate,    urea, sulfonate, sulfone, sulfoxide, sulfonamide, acyl, acyloxy,    trialkylsilyloxy, or acylamino; or-   any two of R¹, R², R³, R⁴, R⁵, and R⁶, together with the carbon    atoms to which they are attached, form an aryl, heteroaryl,    carbocyclyl, or heterocyclyl; or-   any two of R⁷, R⁸, R⁹, R¹⁰, and R¹¹, together with the carbon atoms    to which they are attached, form an aryl, heteroaryl, carbocyclyl,    or heterocyclyl; and R¹² is H, alkyl or aralkyl.

In some embodiments, each instance of R², R³, R⁴, and R⁵ isindependently unsubstituted alkyl or alkyl substituted with one or moresubstituents selected from hydroxy, alkoxy, acyloxy, amino, and thio.

In some embodiments, the compound has a structure of formula IA:

In other embodiments, the compound has a structure of formula IB:

In some embodiments, the transition metal catalyst comprises an iridiumcomplex, e.g., a catalyst prepared by combining an iridium source and aligand (e.g., a chiral ligand). In some embodiments, the iridium sourceis selected from (acetylacetonato)(1,5-cyclooctadiene)iridium(I),(acetylacetonato)(1,5-cyclooctadiene)iridium(I),(acetylacetonato)dicarbonyliridium(I),bis[1,2-bis(diphenylphosphino)ethane]carbonyl chloroiridium(I),bis(1,5-cyclooctadiene)diiridium(I) dichloride,bis(1,5-cyclooctadiene)iridium(I) tetrafluoroborate,bis(cyclooctadiene)iridium(I)tetrakis(3,5-bis(trifluoromethyl)phenyl)borate,chlorobis(cyclooctene)iridium(I)dimer,(1,5-cyclooctadiene)bis(methyldiphenylphosphine)iridium(I)hexafluorophosphate,(1,5-cyclooctadiene)(hexafluoroacetylacetonato)iridium(I),(1,5-cyclooctadiene)-η5-indenyl)iridium(I),(1,5-cyclooctadiene)(methoxy)iridium(I) dimer,(1,5-cyclooctadiene)(pyridine)(tricyclohexylphosphine)-iridium(I)hexafluorophosphate,(1,5-cyclooctadiene)(pyridine)(tricyclohexylphosphine)-iridium(I)hexafluorophosphate, and(1,5-cyclooctadiene)(pyridine)(tricyclohexylphosphine)iridium(I)tetrakis[3,5-bis(trifluoromethyl)phenyl]borate. In certain preferredembodiments, the iridium source is bis(1,5-cyclooctadiene)diiridium(I)dichloride.

In some embodiments, the chiral ligand comprises a diphosphine ligand,preferably a ferrocenyl diphosphine ligand. In some embodiments, thediphosphine ligand is selected from S—(CF₃)-t-BuPHOX, S,S-Et-FerroTANE,S,R_(P)-xyliphos, or S,R_(P)-BTFM-xyliphos, R—(CF₃)-t-BuPHOX,R,R-Et-FerroTANE, R,S_(P)-xyliphos, and R,S_(P)-BTFM-xyliphos. Incertain preferred embodiments, the chiral ligand isS,R_(P)-BTFM-xyliphos or R,S_(P)-BTFM-xyliphos.

In some embodiments, the transition metal catalyst is a chiraltransition metal catalyst and is used in an amount from about 0.1 mol %to about 100 mol % relative to the compound of formula (II) or (VII). Inother embodiments, the transition metal catalyst is a chiral transitionmetal catalyst and is used in an amount from about 5 mol % to about 30mol % relative to the compound of formula (II) or (VII). In certainembodiments, the iridium catalyst is used in an amount of about 20 mol %relative to the compound of formula (II) or (VII).

In some embodiments, the compound of formula (I) or (VIII) has about 70%ee or greater, about 80% ee or greater, about 85% ee or greater, about88% ee or greater, about 90% ee or greater, about 91% ee or greater,about 92% ee or greater, about 93% ee or greater, about 94% ee orgreater, about 95% ee or greater, about 96% ee or greater, about 97% eeor greater, about 98% ee or greater, or about 99% ee or greater.

In another aspect, the present disclosure provides a method of preparinga compound of Formula (II):

comprising reacting a compound of Formula (III):

a compound of Formula (IV):

and

-   a transition metal catalyst under cross-coupling conditions,    wherein, as valence and stability permit:-   R¹ and R⁷ are each independently hydrogen, hydroxyl, halogen, nitro,    alkyl, alkenyl, alkynyl, cyano, carboxyl, sulfate, amino, alkoxy,    alkylamino, alkylthio, ether, thioether, ester, amide, thioester,    carbonate, carbamate, urea, sulfonate, sulfone, sulfoxide,    sulfonamide, acyl, acyloxy, alkylsilyloxy, or acylamino;-   each instance of R², R³, R⁴, R⁵, R⁸, R⁹, R¹⁰, and R¹¹ is    independently hydrogen, hydroxyl, halogen, nitro, alkyl, alkenyl,    alkynyl, cyano, carboxyl, sulfate, amino, alkoxy, alkylamino,    alkylthio, ether, thioether, ester, amide, thioester, carbonate,    carbamate, urea, sulfonate, sulfone, sulfoxide, sulfonamide, acyl,    acyloxy, alkylsilyloxy, acylamino, aryl, heteroaryl, carbocyclyl, or    heterocyclyl;-   R⁶ is hydrogen, hydroxyl, halogen, nitro, alkyl, alkenyl, alkynyl,    cyano, carboxyl, sulfate, amino, alkoxy, alkylamino, alkylthio,    ether, thioether, ester, amide, thioester, carbonate, carbamate,    urea, sulfonate, sulfone, sulfoxide, sulfonamide, acyl, acyloxy,    alkylsilyloxy, or acylamino; or-   any two of R¹, R², R³, R⁴, R⁵, and R⁶, together with the carbon    atoms to which they are attached, form an aryl, heteroaryl,    carbocyclyl, or heterocyclyl; or-   any two of R⁷, R⁸, R⁹, R¹⁰, and R¹¹, together with the carbon atoms    to which they are attached, form an aryl, heteroaryl, carbocyclyl,    or heterocyclyl; and-   R¹³ and R¹⁴ are each independently hydroxyl, nitro, cyano, carboxyl,    sulfate, amino, alkoxy, alkylamino, alkylthio, ether, thioether,    ester, amide, thioester, carbonate, carbamate, urea, sulfonate,    sulfone, sulfoxide, sulfonamide, acyl, acyloxy, alkylsilyloxy, or    acylamino.

In some embodiments, R¹³ and R¹⁴ are each independently unsubstitutedalkyl or alkyl substituted with one or more substituents selected fromhydroxy, alkoxy, acyloxy, amino and thio. In certain embodiments, R¹⁴ ishydroxyalkyl.

In some embodiments, the transition metal catalyst comprises a nickel(e.g., Ni(COD)₂), palladium, or platinum catalyst. In certainembodiments, the transition metal catalyst comprises a palladiumcatalyst. In some embodiments, the palladium catalyst is selected fromPd/C, Pd₂(DBA)₃, Pd(PPh₃)₄, Pd(OC(O)R^(C))₂, Pd(OAc)₂, PdCl₂,Pd(PhCN)₂Cl₂, Pd(CH₃CN)₂Cl₂, PdBr₂, Pd(acac)₂, [Pd(allyl)Cl]₂, Pd(TFA)₂,Pd₂(pmdba)₃, Pd(P(t-Bu)₂Me)₂, and pre-formed Pd(II)-ligand complexes;wherein R^(C) is optionally substituted alkyl, alkenyl, alkynyl, aryl,heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, heterocycloalkyl,(cycloalkyl)alkyl, or (heterocycloalkyl)alkyl. In certain preferredembodiments, the palladium catalyst is Pd(P(t-Bu)₂Me)₂. In someembodiments, the transition metal catalyst is used in an amount fromabout 0.5 mol % to about 50 mol % relative to the compound of formula(III) or (IV).

In some embodiments, R¹ is hydrogen. In other embodiments, R¹ isunsubstituted alkyl or alkyl substituted with one or more substituentsselected from hydroxy, alkoxy, acyloxy, amino, and thio. In someembodiments, R² is selected from H, halo and hydroxy. In someembodiments, R³ is alkyl. In other embodiments, R⁵ is hydroxy or alkoxy.In some embodiments, R⁶ is unsubstituted alkyl or alkyl substituted withone or more substituents selected from hydroxy, alkoxy, acyloxy, aminoand thio. In some embodiments, R⁶ is hydroxyalkyl or acyloxyalkyl,preferably CH₂OH.

In some embodiments, R⁷ is unsubstituted alkyl or alkyl substituted withone or more substituents selected from hydroxy, alkoxy, acyloxy, amino,and thio. In other embodiments, R⁷ is H, halo or hydroxy. In someembodiments, R⁸ is alkoxy. In some embodiments, R⁹ is alkyl. In certainembodiments, R¹⁰ is hydroxy or alkoxy. In some embodiments, is H.

In some embodiments, each instance of R², R³, R⁴, R⁵, R⁸, R⁹, R¹⁰, andR¹¹ is independently unsubstituted alkyl or alkyl substituted with oneor more substituents selected from hydroxy, alkoxy, acyloxy, amino, andthio.

In other embodiments, the present disclosure provides a compound ofFormula (V):

wherein:

-   R¹ and Rare each independently hydrogen, carbonyl, thiocarbonyl,    imine, oxime, hydroxyl, halogen, nitro, alkyl, alkenyl, alkynyl,    cyano, carboxyl, sulfate, amino, alkoxy, alkylamino, alkylthio,    ether, thioether, ester, amide, thioester, carbonate, carbamate,    urea, sulfonate, sulfone, sulfoxide, sulfonamide, acyl, acyloxy,    alkylsilyloxy, or acylamino;-   each instance of R², R³, R⁴, and R⁵ is independently hydrogen,    carbonyl, thiocarbonyl, imine, oxime, hydroxyl, halogen, nitro,    alkyl, alkenyl, alkynyl, cyano, carboxyl, sulfate, amino, alkoxy,    alkylamino, alkylthio, ether, thioether, ester, amide, thioester,    carbonate, carbamate, urea, sulfonate, sulfone, sulfoxide,    sulfonamide, acyl, acyloxy, alkylsilyloxy, acylamino, aryl,    heteroaryl, carbocyclyl, or heterocyclyl;-   each instance of R⁸, R⁹, R¹⁰, and R¹¹ is independently hydrogen,    carbonyl, thiocarbonyl, hydroxyl, halogen, nitro, alkyl, alkenyl,    alkynyl, cyano, carboxyl, sulfate, amino, alkoxy, alkylamino,    alkylthio, ether, thioether, ester, amide, thioester, carbonate,    carbamate, urea, sulfonate, sulfone, sulfoxide, sulfonamide, acyl,    acyloxy, alkylsilyloxy, acylamino, aryl, heteroaryl, carbocyclyl, or    heterocyclyl;-   R⁶ is hydrogen, hydroxyl, halogen, nitro, alkyl, alkenyl, alkynyl,    cyano, carboxyl, sulfate, amino, alkoxy, alkylamino, alkylthio,    ether, thioether, ester, amide, thioester, carbonate, carbamate,    urea, sulfonate, sulfone, sulfoxide, sulfonamide, acyl, acyloxy,    alkylsilyloxy, or acylamino; or-   any two of R¹, R², R³, R⁴, R⁵, and R⁶, together with the carbon    atoms to which they are attached, form an aryl, heteroaryl,    carbocyclyl, or heterocyclyl; or-   any two of R⁷, R⁸, R⁹, R¹⁰, and R¹¹, together with the carbon atoms    to which they are attached, form an aryl, heteroaryl, carbocyclyl,    or heterocyclyl;-   R¹⁵ is hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, carboxyl,    sulfate, amino, alkoxy, alkylamino, alkylthio, sulfonate, sulfone,    sulfoxide, acyl, acylamino, aryl, heteroaryl, carbocyclyl,    heterocyclyl, aralkyl, aralkyloxy, hetaralkyl, carbocyclylalkyl, or    heterocyclylalkyl; and-   X is hydrogen, oxo (═O), ═S, ═NH, ═N-alkyl, ═NOH, hydroxyl, halogen,    nitro, alkyl, alkenyl, alkynyl, cyano, carboxyl, sulfate, amino,    alkoxy, alkylamino, alkylthio, ether, thioether, ester, amide,    thioester, carbonate, carbamate, urea, sulfonate, sulfone,    sulfoxide, sulfonamide, acyl, acyloxy, alkylsilyloxy, acylamino,    aryl, heteroaryl, carbocyclyl, heterocyclyl, aralkyl, aralkyloxy,    hetaralkyl, carbocyclylalkyl, or heterocyclylalkyl;-   or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound has the formula (VA):

In other embodiments, the compound has the formula (VB):

In still other embodiments, the compound has the Formula (VI):

In yet other embodiments, the compound has the Formula (VIA):

In other embodiments, the compound has the Formula (VIB):

In some embodiments, R¹, R⁶, and R⁷ are each unsubstituted alkyl oralkyl substituted with one or more substituents selected from hydroxy,alkoxy, acyloxy, amino, and thio. In some embodiments, each instance ofR², R³, R⁴, R⁵, R⁸, R⁹, R¹¹, and R¹¹ is independently unsubstitutedalkyl or alkyl substituted with one or more substituents selected fromhydroxy, alkoxy, acyloxy, amino, and thio.

In some embodiments, R¹⁵ is H or alkyl. In certain embodiments, R¹⁵ isunsubstituted alkyl or alkyl substituted with one or more substituentsselected from hydroxy, alkoxy, acyloxy, amino, and thio. In preferredembodiments, R¹⁵ is methyl. In some embodiments, X is unsubstitutedalkyl or alkyl substituted with one or more substituents selected fromhydroxy, alkoxy, acyloxy, amino, and thio.

In some embodiments, each R³, R⁴, R⁸, or R⁹ is independently carbonyl,halogen, nitro, cyano, carboxyl, sulfate, amino, alkoxy, alkylamino,ester, sulfonate, sulfone, sulfoxide, acyl, haloalkyl or acyloxy. Incertain embodiments, each R³, R⁴, R⁸, or R⁹ is independently carbonyl,halogen, nitro, cyano, carboxyl, ester, acyl, haloalkyl or acyloxy.

In certain embodiments, the compound may be a prodrug, e.g., wherein ahydroxyl in the parent compound is presented as an ester or a carbonate,a carboxylic acid present in the parent compound is presented as anester, or an amino group is presented as an amide. In certain suchembodiments, the prodrug is metabolized to the active parent compound invivo (e.g., the ester is hydrolyzed to the corresponding hydroxyl orcarboxylic acid).

In certain embodiments, compounds of the invention may be racemic. Incertain embodiments, compounds of the invention may be enriched in oneenantiomer. For example, a compound of the invention may have greaterthan 30% ee, 40% ee, 50% ee, 60% ee, 70% ee, 80% ee, 90% ee, 95% ee, 96%ee, 97% ee, 98% ee, 99% or greater ee. The compounds of the inventionhave more than one stereocenter.

Accordingly, the compounds of the invention may be enriched in one ormore diastereomers. For example, a compound of the invention may havegreater than 30% de, 40% de, 50% de, 60% de, 70% de, 80% de, 90% de, 95%de, 96% de, 97% de, 98% de, 99% or greater de. In certain embodiments,the compounds of the invention have substantially one isomericconfiguration at one or more stereogenic centers, and have multipleisomeric configurations at the remaining stereogenic centers.

In certain embodiments, a therapeutic preparation of the compound of theinvention may be enriched to provide predominantly one enantiomer of acompound. An enantiomerically enriched mixture may comprise, forexample, at least 60 mol percent of one enantiomer, or more preferablyat least 75, 90, 95, or even 99 mol percent. In certain embodiments, thecompound enriched in one enantiomer is substantially free of the otherenantiomer, wherein substantially free means that the substance inquestion makes up less than 10%, or less than 5%, or less than 4%, orless than 3%, or less than 2%, or less than 1% as compared to the amountof the other enantiomer, e.g., in the composition or compound mixture.For example, if a composition or compound mixture contains 98 grams of afirst enantiomer and 2 grams of a second enantiomer, it would be said tocontain 98 mol percent of the first enantiomer and only 2% of the secondenantiomer. In certain embodiments, a therapeutic preparation may beenriched to provide predominantly one diastereomer of the compound ofthe invention. A diastereomerically enriched mixture may comprise, forexample, at least 60 mol percent of one diastereomer, or more preferablyat least 75, 90, 95, or even 99 mol percent.

In certain embodiments, the bis-THIQcompounds of the invention exhibitan improved pharmacokinetic profile relative to existing bis-THIQs.

In certain embodiments, the bis-THIQ compounds of the invention exhibitimproved bioavailability relative to existing bis-THIQs.

Transition Metal Catalysts

Preferred transition metal catalysts of the invention are complexes ofiridium. In some embodiments, the transition metal catalyst is aniridium catalyst.

In some embodiments, the iridium catalyst is prepared by combining aniridium source and a chiral ligand. In preferred embodiments the iridiumcatalyst is prepared by combining an iridium source and a chiral ligand.

Exemplary iridium sources that may be used in the methods of theinvention include, but are not limited to,(acetylacetonato)(1,5-cyclooctadiene)iridium(I),(acetylacetonato)(1,5-cyclooctadiene)iridium(I),(acetylacetonato)dicarbonyliridium(I),bis[1,2-bis(diphenylphosphino)ethane]carbonyl chloroiridium(I),bis(1,5-cyclooctadiene)diiridium(I) dichloride,bis(1,5-cyclooctadiene)iridium(I) tetrafluoroborate,bis(cyclooctadiene)iridium(I)tetrakis(3,5-bis(trifluoromethyl)phenyl)borate,chlorobis(cyclooctene)iridium(I)dimer,(1,5-cyclooctadiene)bis(methyldiphenylphosphine)iridium(I)hexafluorophosphate,(1,5-cyclooctadiene)(hexafluoroacetylacetonato)iridium(I),(1,5-cyclooctadiene)-η5-indenyl)iridium(I),(1,5-cyclooctadiene)(methoxy)iridium(I) dimer,(1,5-cyclooctadiene)(pyridine)(tricyclohexylphosphine)-iridium(I)hexafluorophosphate,(1,5-cyclooctadiene)(pyridine)(tricyclohexylphosphine)-iridium(I)hexafluorophosphate, and(1,5-cyclooctadiene)(pyridine)(tricyclohexylphosphine)iridium(I)tetrakis[3,5-bis(trifluoromethyl)phenyl]borate. In preferredembodiments, the iridium source is bis(1,5-cyclooctadiene)diiridium(I)dichloride.

Accordingly, when describing the amount of transition metal catalystused in the methods of the invention, the following terminology applies.The amount of transition metal catalyst present in a reaction isalternatively referred to herein as “catalyst loading”. Catalyst loadingmay be expressed as a percentage that is calculated by dividing themoles of catalyst complex by the moles of the substrate present in agiven reaction. Catalyst loading is alternatively expressed as apercentage that is calculated by dividing the moles of total transitionmetal (for example, iridium) by the moles of the substrate present in agiven reaction.

In certain embodiments, the transition metal catalyst is present underthe conditions of the reaction from an amount of about 0.01 mol % toabout 30 mol % total iridium relative to the substrate, such as thecompound of formula (II) or (VII). In certain embodiments, the catalystloading is from about 0.05 mol % to about 25 mol % total iridiumrelative to the substrate. In certain embodiments, the catalyst loadingis from about 0.1 mol % to about 25 mol %, about 1 mol % to about 25 mol% about 5 mol % to about 22 mol % about 10 mol % to about 20 mol %,about 15 mol % to about 20 moltotal iridium relative to the substrate.In preferred embodiments, the catalyst loading is about 20 mol % totaliridium.

Chiral Ligands

One aspect of the invention relates to the enantioselectivity of themethods. Enantioselectivity results from the use of chiral ligandsduring the hydrogenation reaction. Accordingly, the iridium catalystcomprises a chiral ligand. Without being bound by theory, the asymmetricenvironment that is created around the metal center by the presence ofchiral ligands produces an enantioselective reaction. The chiral ligandforms a complex with the transition metal (i.e., iridium), therebyoccupying one or more of the coordination sites on the metal andcreating an asymmetric environment around the metal center. Thiscomplexation may or may not involve the displacement of achiral ligandsalready complexed to the metal. When displacement of one or more achiralligands occurs, the displacement may proceed in a concerted fashion,i.e., with both the achiral ligand decomplexing from the metal and thechiral ligand complexing to the metal in a single step. Alternatively,the displacement may proceed in a stepwise fashion, i.e., withdecomplexing of the achiral ligand and complexing of the chiral ligandoccurring in distinct steps. Complexation of the chiral ligand to thetransition metal may be allowed to occur in situ, i.e., by admixing theligand and metal before adding the substrate. Alternatively, theligand-metal complex can be formed separately, and the complex isolatedbefore use in the alkylation reactions of the present invention.

Once coordinated to the transition metal center, the chiral ligandinfluences the orientation of other molecules as they interact with thetransition metal catalyst. Coordination of the metal center with aπ-allyl group and reaction of the substrate with the π-allyl-metalcomplex are dictated by the presence of the chiral ligand. Theorientation of the reacting species determines the stereochemistry ofthe products.

Chiral ligands of the invention may be bidentate or monodentate or,alternatively, ligands with higher denticity (e.g., tridentate,tetradentate, etc.) can be used. In preferred embodiments, the ligand isa bidentate ligand. Additionally, it is preferred that the ligand besubstantially enantiopure. By “enantiopure” is meant that only a singleenantiomer is present. In many cases, substantially enantiopure ligands(e.g., ee>99%, preferably ee>99.5%, even more preferably ee>99.9%) canbe purchased from commercial sources, obtained by successiverecrystallizations of an enantioenriched substance, or by other suitablemeans for separating enantiomers.

Exemplary chiral ligands may be found in U.S. Pat. No. 7,863,443 and CNPatent No. 105524111B, the entireties of which are incorporated hereinby reference. In certain embodiments, the chiral ligand is anenantioenriched phosphine ligand. In certain embodiments, theenantioenriched phosphorus-based ligand is a phosphoramidite ligand. Incertain such embodiments, the transition metal complex with the ligandcomprises S—(CF₃)-t-BuPHOX, S,S-Et-FerroTANE, S,R_(P)-Xyliphos, orS,R_(P)-BTFM-xyliphos. In other embodiments, the transition metalcomplex with the ligand comprises R—(CF₃)-t-BuPHOX, R,R-Et-FerroTANE,R,S_(P)-Xyliphos, or R,S_(P)-BTFM-xyliphos.

Generally, the chiral ligand is present in an amount in the range ofabout 1 equivalent to about 20 equivalents relative to the amount oftotal metal from the catalyst, preferably in the range of about 1 toabout 15 equivalents relative to the amount of total metal from thecatalyst, and most preferably about 1 equivalent relative to the amountof total metal from the catalyst. Alternatively, the amount of thechiral ligand can be measured relative to the amount of the substrate.

In certain embodiments, the ligand is present under the conditions ofthe reaction from an amount of about 5 mol % to about 80 mol % relativeto the substrate, e.g., the compound of formula (II) or formula (VII).The amount of the chiral ligand present in the reaction is alternativelyreferred to herein as “ligand loading” and is expressed as a percentagethat is calculated by dividing the moles of ligand by the moles of thesubstrate present in a given reaction. In certain embodiments, theligand loading is from about 5 mol %, about 6 mol %, about 7 mol %,about 10 mol %, about 12 mol %, about 14 mol %, about 16 mol %, about 18mol %, about 19 mol %, about 19.5 mol %, about 19.8 mol %, about 20 mol%, about 20.2 mol %, about 20.5 mol %, about 20.8 mol %, about 21 mol %,about 21.2 mol %, about 21.4 mol %, about 21.8 mol %, about 22 mol %,about 25 mol %, about 28 mol %, about 30 mol %, about 35 mol %, about 40mol %, about 45 mol %, about 50 mol %, about 55 mol %, about 58 mol %,about 60 mol %, or about 70 mol %. In preferred embodiments, the ligandloading is 21 mol %.

Where a chiral ligand is used, the reactions of the invention may createmultiple stereocenters in the product compound, such as the compound ofFormula (I), (V) or (VI), in a high degree of enantiomeric excess (ee).The ee of a compound may be measured by dividing the difference in thefractions of the enantiomers by the sum of the fractions of theenantiomers. For example, if a compound is found to comprise 98%(S)-enantiomer, and 2% (R) enantiomer, then the ee of the compound is(98−2)/(98+2), or 96%. In certain embodiments, the compound of formula(I), (V) or (VI) has about 30% ee or greater, about 40% ee or greater,about 50% ee or greater, 60% ee or greater, about 70% ee or greater,about 80% ee or greater, about 85% ee or greater, about 88% ee orgreater, about 90% ee or greater, about 91% ee or greater, about 92% eeor greater, about 93% ee or greater, about 94% ee or greater, about 95%ee or greater, about 96% ee or greater, about 97% ee or greater, about98% ee or greater, or about 99% ee or greater, even where this % ee isgreater than the % ee of the starting material, such as 0% ee (racemic).

Methods of Treatment

In certain embodiments, the present disclosure provides methods fortreating or preventing cancer, comprising administering to a subject inneed thereof a therapeutically effective amount of a compound of theinvention (e.g., a compound of Formula V, VA, VB, VI, VIA, or VIB), or apharmaceutical composition comprising said compound.

In certain embodiments, the cancer that is treated by the methods of theinvention is Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia(AML), Adrenocortical Carcinoma, Anal Cancer, Appendix Cancer, AtypicalTeratoid/Rhabdoid Tumor, Basal Cell Carcinoma, Bile Duct Cancer, BladderCancer, Bone Cancer, Brain Tumor, Astrocytoma, Brain and Spinal CordTumor, Brain Stem Glioma, Central Nervous System AtypicalTeratoid/Rhabdoid Tumor, Central Nervous System Embryonal Tumors, BreastCancer, Bronchial Tumors, Burkitt Lymphoma, Carcinoid Tumor, Carcinomaof Unknown Primary, Central Nervous System Cancer, Cervical Cancer,Childhood Cancers, Chordoma, Chronic Lymphocytic Leukemia (CLL), ChronicMyelogenous Leukemia (CML), Chronic Myeloproliferative Disorders, ColonCancer, Colorectal Cancer, Craniopharyngioma, Cutaneous T-Cell Lymphoma,Ductal Carcinoma In Situ (DCIS), Embryonal Tumors, Endometrial Cancer,Ependymoblastoma, Ependymoma, Esophageal Cancer, Esthesioneuroblastoma,Ewing Sarcoma, Extracranial Germ Cell Tumor, Extragonadal Germ CellTumor, Extrahepatic Bile Duct Cancer, Eye Cancer, Fibrous Histiocytomaof Bone, Gallbladder Cancer, Gastric Cancer, Gastrointestinal CarcinoidTumor, Gastrointestinal Stromal Tumors (GIST), Germ Cell Tumor,Extracranial Germ Cell Tumor, Extragonadal Germ Cell Tumor, Ovarian GermCell Tumor, Gestational Trophoblastic Tumor, Glioma, Hairy CellLeukemia, Head and Neck Cancer, Heart Cancer, Hepatocellular Cancer,Histiocytosis, Langerhans Cell Cancer, Hodgkin Lymphoma, HypopharyngealCancer, Intraocular Melanoma, Islet Cell Tumors, Kaposi Sarcoma, KidneyCancer, Langerhans Cell Histiocytosis, Laryngeal Cancer, Leukemia, Lipand Oral Cavity Cancer, Liver Cancer, Lobular Carcinoma In Situ (LCIS),Lung Cancer, Lymphoma, AIDS-Related Lymphoma, Macroglobulinemia, MaleBreast Cancer, Medulloblastoma, Medulloepithelioma, Melanoma, MerkelCell Carcinoma, Malignant Mesothelioma, Metastatic Squamous Neck Cancerwith Occult Primary, Midline Tract Carcinoma Involving NUT Gene, MouthCancer, Multiple Endocrine Neoplasia Syndrome, Multiple Myeloma/PlasmaCell Neoplasm, Mycosis Fungoides, Myelodysplastic Syndrome,Myelodysplastic/Myeloproliferative Neoplasm, Chronic MyelogenousLeukemia (CML), Acute Myeloid Leukemia (AML), Myeloma, Multiple Myeloma,Chronic Myeloproliferative Disorder, Nasal Cavity Cancer, ParanasalSinus Cancer, Nasopharyngeal Cancer, Neuroblastoma, Non-HodgkinLymphoma, Non-Small Cell Lung Cancer, Oral Cancer, Oral Cavity Cancer,Lip Cancer, Oropharyngeal Cancer, Osteosarcoma, Ovarian Cancer,Pancreatic Cancer, Papillomatosis, Paraganglioma, Paranasal SinusCancer, Nasal Cavity Cancer, Parathyroid Cancer, Penile Cancer,Pharyngeal Cancer, Pheochromocytoma, Pineal Parenchymal Tumors ofIntermediate Differentiation, Pineoblastoma, Pituitary Tumor, PlasmaCell Neoplasm, Pleuropulmonary Blastoma, Breast Cancer, Primary CentralNervous System (CNS) Lymphoma, Prostate Cancer, Rectal Cancer, RenalCell Cancer, Renal Pelvis Cancer, Ureter Cancer, Transitional CellCancer, Retinoblastoma, Rhabdomyosarcoma, Salivary Gland Cancer,Sarcoma, Sézary Syndrome, Skin Cancer, Small Cell Lung Cancer, SmallIntestine Cancer, Soft Tissue Sarcoma, Squamous Cell Carcinoma, SquamousNeck Cancer with Occult Primary, Stomach Cancer, SupratentorialPrimitive Neuroectodermal Tumors, T-Cell Lymphoma, Testicular Cancer,Throat Cancer, Thymoma, Thymic Carcinoma, Thyroid Cancer, TransitionalCell Cancer of the Renal Pelvis and Ureter, Gestational TrophoblasticTumor, Unknown Primary, Unusual Cancer of Childhood, Urethral Cancer,Uterine Cancer, Uterine Sarcoma, Waldenström Macroglobulinemia, or WilmsTumor.

In certain embodiments, the cancer that is treated by the methods of theinvention is a variety of acute myeloid leukemia (AML), bladder cancer,breast cancer, colorectal cancer, chronic myelogenous leukemia (CIVIL),esophageal cancer, gastric cancer, lung cancer, melanoma, mesothelioma,non-small cell lung carcinoma (NSCLC), ovarian cancer, pancreaticcancer, prostate cancer, renal cancer, or skin cancer.

In certain embodiments, the cancer that is treated by the methods of theinvention is a variety of acute myeloid leukemia (AML), breast cancer,colorectal cancer, chronic myelogenous leukemia (CML), esophagealcancer, gastric cancer, lung cancer, melanoma, non-small cell lungcarcinoma (NSCLC), pancreatic cancer, prostate cancer, or renal cancer.

In certain embodiments, the cancer is selected from bladder cancer,breast cancer (including TNBC), cervical cancer, colorectal cancer,chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma(DLBCL), esophageal adenocarcinoma, glioblastoma, head and neck cancer,leukemia (acute and chronic), low-grade glioma, lung cancer (includingadenocarcinoma, non-small cell lung cancer, and squamous cellcarcinoma), Hodgkin's lymphoma, non-Hodgkin lymphoma (NHL), melanoma,multiple myeloma (MM), ovarian cancer, pancreatic cancer, prostatecancer, renal cancer (including renal clear cell carcinoma and kidneypapillary cell carcinoma), and stomach cancer.

Combination therapy is an important treatment modality in many diseasesettings, such as cancer. Recent scientific advances have increased ourunderstanding of the pathophysiological processes that underlie theseand other complex diseases. This increased understanding has providedimpetus to develop new therapeutic approaches using combinations ofdrugs directed at multiple therapeutic targets to improve treatmentresponse, minimize development of resistance, or minimize adverseevents. In settings in which combination therapy provides significanttherapeutic advantages, there is growing interest in the development ofcombinations with new investigational drugs, such as bis-THIQs.

When considering the administration of multiple therapeutic agentstogether, one must be concerned about what sort of drug interactionswill be observed. This action can be positive (when the drug's effect isincreased) or antagonistic (when the drug's effect is decreased) or anew side effect can be produced that neither produces on its own.

When the interaction causes an increase in the effects of one or both ofthe drugs the interaction, the degree to which the final effect of thecombined drugs is greater than administering either drug alone can becalculated resulting in what is called the “combination index” (CI)(see, e.g., Chou and Talalay, 1984). A combination index at or around 1is considered “additive”; whereas a value greater than 1 is considered“synergistic”.

The present invention provides methods for combination therapy intreating or preventing cancer comprising an bis-THIQ (e.g., a compoundof the invention) and one or more additional chemotherapeutic agents.

Certain embodiments of the invention relate to treating cancercomprising conjointly administering a chemotherapeutic agent and acompound of the invention.

In certain embodiments, the chemotherapeutic is an immune-stimulatingagent. For example, the immune-stimulating agent may be apro-inflammatory agent.

The chemotherapeutic agent that may be conjointly administered with thebis-THIQs described herein in the methods of the invention includeaminoglutethimide, amsacrine, anastrozole, asparaginase, AZD5363,Bacillus Calmette-Guérin vaccine (bcg), bicalutamide, bleomycin,bortezomib, buserelin, busulfan, campothecin, capecitabine, carboplatin,carfilzomib, carmustine, chlorambucil, chloroquine, cisplatin,cladribine, clodronate, cobimetinib, colchicine, cyclophosphamide,cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin,demethoxyviridin, dexamethasone, dichloroacetate, dienestrol,diethylstilbestrol, docetaxel, doxorubicin, epacadostat, epirubicin,erlotinib, estradiol, estramustine, etoposide, everolimus, exemestane,filgrastim, fludarabine, fludrocortisone, fluorouracil, fluoxymesterone,flutamide, gemcitabine, genistein, goserelin, hydroxyurea, idarubicin,ifosfamide, imatinib, interferon, irinotecan, lenalidomide, letrozole,leucovorin, leuprolide, levamisole, lomustine, lonidamine,mechlorethamine, medroxyprogesterone, megestrol, melphalan,mercaptopurine, mesna, metformin, methotrexate, miltefosine, mitomycin,mitotane, mitoxantrone, MK-2206, nilutamide, nocodazole, octreotide,olaparib, oxaliplatin, paclitaxel, pamidronate, pazopanib, pentostatin,perifosine, plicamycin, pomalidomide, porfimer, procarbazine,raltitrexed, rituximab, rucaparib, selumetinib, sorafenib, streptozocin,sunitinib, suramin, talazoparib, tamoxifen, temozolomide, temsirolimus,teniposide, testosterone, thalidomide, thioguanine, thiotepa, titanocenedichloride, topotecan, trametinib, trastuzumab, tretinoin, veliparib,vinblastine, vincristine, vindesine, or vinorelbine.

In certain embodiments, the chemotherapeutic agent that may beadministered with the bis-THIQs described herein in the methods of theinvention include abagovomab, adecatumumab, afutuzumab, anatumomabmafenatox, apolizumab, atezolizumab, blinatumomab, catumaxomab,durvalumab, epacadostat, epratuzumab, inotuzumab ozogamicin,intelumumab, ipilimumab, isatuximab, lambrolizumab, nivolumab,ocaratuzumab, olatatumab, pembrolizumab, pidilizumab, ticilimumab,samalizumab, or tremelimumab.

In certain embodiments, the chemotherapeutic agent is ipilimumab,nivolumab, pembrolizumab, or pidilizumab.

Many combination therapies have been developed for the treatment ofcancer. In certain embodiments, compounds of the invention may beconjointly administered with a combination therapy. Examples ofcombination therapies with which compounds of the invention may beconjointly administered are included in Table 1.

TABLE 1 Exemplary combinatorial therapies for the treatment of cancer.Name Therapeutic agents ABV Doxorubicin, Bleomycin, Vinblastine ABVDDoxorubicin, Bleomycin, Vinblastine, Dacarbazine AC (Breast)Doxorubicin, Cyclophosphamide AC (Sarcoma) Doxorubicin, Cisplatin AC(Neuroblastoma) Cyclophosphamide, Doxorubicin ACE Cyclophosphamide,Doxorubicin, Etoposide ACe Cyclophosphamide, Doxorubicin AD Doxorubicin,Dacarbazine AP Doxorubicin, Cisplatin ARAC-DNR Cytarabine, DaunorubicinB-CAVe Bleomycin, Lomustine, Doxorubicin, Vinblastine BCVPP Carmustine,Cyclophosphamide, Vinblastine, Procarbazine, Prednisone BEACOPPBleomycin, Etoposide, Doxorubicin, Cyclophosphamide, Vincristine,Procarbazine, Prednisone, Filgrastim BEP Bleomycin, Etoposide, CisplatinBIP Bleomycin, Cisplatin, Ifosfamide, Mesna BOMP Bleomycin, Vincristine,Cisplatin, Mitomycin CA Cytarabine, Asparaginase CABO Cisplatin,Methotrexate, Bleomycin, Vincristine CAF Cyclophosphamide, Doxorubicin,Fluorouracil CAL-G Cyclophosphamide, Daunorubicin, Vincristine,Prednisone, Asparaginase CAMP Cyclophosphamide, Doxorubicin,Methotrexate, Procarbazine CAP Cyclophosphamide, Doxorubicin, CisplatinCaT Carboplatin, Paclitaxel CAV Cyclophosphamide, Doxorubicin,Vincristine CAVE ADD CAV and Etoposide CA-VP16 Cyclophosphamide,Doxorubicin, Etoposide CC Cyclophosphamide, Carboplatin CDDP/VP-16Cisplatin, Etoposide CEF Cyclophosphamide, Epirubicin, FluorouracilCEPP(B) Cyclophosphamide, Etoposide, Prednisone, with or without/Bleomycin CEV Cyclophosphamide, Etoposide, Vincristine CF Cisplatin,Fluorouracil or Carboplatin Fluorouracil CHAP Cyclophosphamide orCyclophosphamide, Altretamine, Doxorubicin, Cisplatin ChlVPPChlorambucil, Vinblastine, Procarbazine, Prednisone CHOPCyclophosphamide, Doxorubicin, Vincristine, Prednisone CHOP-BLEO AddBleomycin to CHOP CISCA Cyclophosphamide, Doxorubicin, CisplatinCLD-BOMP Bleomycin, Cisplatin, Vincristine, Mitomycin CMF Methotrexate,Fluorouracil, Cyclophosphamide CMFP Cyclophosphamide, Methotrexate,Fluorouracil, Prednisone CMF VP Cyclophosphamide, Methotrexate,Fluorouracil, Vincristine, Prednisone CMV Cisplatin, Methotrexate,Vinblastine CNF Cyclophosphamide, Mitoxantrone, Fluorouracil CNOPCyclophosphamide, Mitoxantrone, Vincristine, Prednisone COB Cisplatin,Vincristine, Bleomycin CODE Cisplatin, Vincristine, Doxorubicin,Etoposide COMLA Cyclophosphamide, Vincristine, Methotrexate, Leucovorin,Cytarabine COMP Cyclophosphamide, Vincristine, Methotrexate, PrednisoneCooper Regimen Cyclophosphamide, Methotrexate, Fluorouracil,Vincristine, Prednisone COP Cyclophosphamide, Vincristine, PrednisoneCOPE Cyclophosphamide, Vincristine, Cisplatin, Etoposide COPPCyclophosphamide, Vincristine, Procarbazine, Prednisone CP(ChronicChlorambucil, Prednisone lymphocytic leukemia) CP (Ovarian Cancer)Cyclophosphamide, Cisplatin CT Cisplatin, Paclitaxel CVD Cisplatin,Vinblastine, Dacarbazine CVI Carboplatin, Etoposide, Ifosfamide, MesnaCVP Cyclophosphamide, Vincristine, Prednisome CVPP Lomustine,Procarbazine, Prednisone CYVADIC Cyclophosphamide, Vincristine,Doxorubicin, Dacarbazine DA Daunorubicin, Cytarabine DAT Daunorubicin,Cytarabine, Thioguanine DAV Daunorubicin, Cytarabine, Etoposide DCTDaunorubicin, Cytarabine, Thioguanine DHAP Cisplatin, Cytarabine,Dexamethasone DI Doxorubicin, Ifosfamide DTIC/Tamoxifen Dacarbazine,Tamoxifen DVP Daunorubicin, Vincristine, Prednisone EAP Etoposide,Doxorubicin, Cisplatin EC Etoposide, Carboplatin EFP Etoposie,Fluorouracil, Cisplatin ELF Etoposide, Leucovorin, Fluorouracil EMA 86Mitoxantrone, Etoposide, Cytarabine EP Etoposide, Cisplatin EVAEtoposide, Vinblastine FAC Fluorouracil, Doxorubicin, CyclophosphamideFAM Fluorouracil, Doxorubicin, Mitomycin FAMTX Methotrexate, Leucovorin,Doxorubicin FAP Fluorouracil, Doxorubicin, Cisplatin F-CL Fluorouracil,Leucovorin FEC Fluorouracil, Cyclophosphamide, Epirubicin FEDFluorouracil, Etoposide, Cisplatin FL Flutamide, Leuprolide FZFlutamide, Goserelin acetate implant HDMTX Methotrexate, LeucovorinHexa-CAF Altretamine, Cyclophosphamide, Methotrexate, Fluorouracil ICE-TIfosfamide, Carboplatin, Etoposide, Paclitaxel, Mesna IDMTX/6-MPMethotrexate, Mercaptopurine, Leucovorin IE Ifosfamide, Etoposie, MesnaIfoVP Ifosfamide, Etoposide, Mesna IPA Ifosfamide, Cisplatin,Doxorubicin M-2 Vincristine, Carmustine, Cyclophosphamide, Prednisone,Melphalan MAC-III Methotrexate, Leucovorin, Dactinomycin,Cyclophosphamide MACC Methotrexate, Doxorubicin, Cyclophosphamide,Lomustine MACOP-B Methotrexate, Leucovorin, Doxorubicin,Cyclophosphamide, Vincristine, Bleomycin, Prednisone MAID Mesna,Doxorubicin, Ifosfamide, Dacarbazine m-BACOD Bleomycin, Doxorubicin,Cyclophosphamide, Vincristine, Dexamethasone, Methotrexate, LeucovorinMBC Methotrexate, Bleomycin, Cisplatin MC Mitoxantrone, Cytarabine NIFMethotrexate, Fluorouracil, Leucovorin MICE Ifosfamide, Carboplatin,Etoposide, Mesna MINE Mesna, Ifosfamide, Mitoxantrone, Etoposidemini-BEAM Carmustine, Etoposide, Cytarabine, Melphalan MOBP Bleomycin,Vincristine, Cisplatin, Mitomycin MOP Mechlorethamine, Vincristine,Procarbazine MOPP Mechlorethamine, Vincristine, Procarbazine, PrednisoneMOPP/ABV Mechlorethamine, Vincristine, Procarbazine, Prednisone,Doxorubicin, Bleomycin, Vinblastine MP (multiple myeloma) Melphalan,Prednisone MP (prostate cancer) Mitoxantrone, Prednisone MTX/6-MOMethotrexate, Mercaptopurine MTX/6-MP/VP Methotrexate, Mercaptopurine,Vincristine, Prednisone MTX-CDDPAdr Methotrexate, Leucovorin, Cisplatin,Doxorubicin MV (breast cancer) Mitomycin, Vinblastine MV (acutemyelocytic Mitoxantrone, Etoposide leukemia) M-VAC MethotrexateVinblastine, Doxorubicin, Cisplatin MVP Mitomycin Vinblastine, CisplatinMVPP Mechlorethamine, Vinblastine, Procarbazine, Prednisone NFLMitoxantrone, Fluorouracil, Leucovorin NOVP Mitoxantrone, Vinblastine,Vincristine OPA Vincristine, Prednisone, Doxorubicin OPPA AddProcarbazine to OPA. PAC Cisplatin, Doxorubicin PAC-I Cisplatin,Doxorubicin, Cyclophosphamide PA-CI Cisplatin, Doxorubicin PCPaclitaxel, Carboplatin or Paclitaxel, Cisplatin PCV Lomustine,Procarbazine, Vincristine PE Paclitaxel, Estramustine PFL Cisplatin,Fluorouracil, Leucovorin POC Prednisone, Vincristine, Lomustine ProMACEPrednisone, Methotrexate, Leucovorin, Doxorubicin, Cyclophosphamide,Etoposide ProMACE/cytaBOM Prednisone, Doxorubicin, Cyclophosphamide,Etoposide, Cytarabine, Bleomycin, Vincristine, Methotrexate, Leucovorin,Cotrimoxazole PRoMACE/MOPP Prednisone, Doxorubicin, Cyclophosphamide,Etoposide, Mechlorethamine, Vincristine, Procarbazine, Methotrexate,Leucovorin Pt/VM Cisplatin, Teniposide PVA Prednisone, Vincristine,Asparaginase PVB Cisplatin, Vinblastine, Bleomycin PVDA Prednisone,Vincristine, Daunorubicin, Asparaginase SMF Streptozocin, Mitomycin,Fluorouracil TAD Mechlorethamine, Doxorubicin, Vinblastine, Vincristine,Bleomycin, Etoposide, Prednisone TCF Paclitaxel, Cisplatin, FluorouracilTIP Paclitaxel, Ifosfamide, Mesna, Cisplatin TTT Methotrexate,Cytarabine, Hydrocortisone Topo/CTX Cyclophosphamide, Topotecan, MesnaVAB-6 Cyclophosphamide, Dactinomycin, Vinblastine, Cisplatin, BleomycinVAC Vincristine, Dactinomycin, Cyclophosphamide VACAdr Vincristine,Cyclophosphamide, Doxorubicin, Dactinomycin, Vincristine VADVincristine, Doxorubicin, Dexamethasone VATH Vinblastine, Doxorubicin,Thiotepa, Flouxymesterone VBAP Vincristine, Carmustine, Doxorubicin,Prednisone VBCMP Vincristine, Carmustine, Melphalan, Cyclophosphamide,Prednisone VC Vinorelbine, Cisplatin VCAP Vincristine, Cyclophosphamide,Doxorubicin, Prednisone VD Vinorelbine, Doxorubicin VelP Vinblastine,Cisplatin, Ifosfamide, Mesna VIP Etoposide, Cisplatin, Ifosfamide, MesnaName Therapeutic agents VM Mitomycin, Vinblastine VMCP Vincristine,Melphalan, Cyclophosphamide, Prednisone VP Etoposide, Cisplatin V-TADEtoposide, Thioguanine, Daunorubicin, Cytarabine 5 + 2 Cytarabine,Daunorubicin, Mitoxantrone 7 + 3 Cytarabine with Daunorubicin orIdarubicin or Mitoxantrone “8 in 1” Methylprednisolone, Vincristine,Lomustine, Procarbazine, Hydroxyurea, Cisplatin, Cytarabine, Dacarbazine

Immune-targeted agents (also known as immuno-oncology agents) actagainst tumors by modulating immune cells. The field of cancerimmunotherapy is rapidly growing, with new targets constantly beingidentified (Chen and Mellman, 2013; Morrissey et al., 2016; Kohrt etal., 2016).

Examples of immuno-oncology agents comprise agents that modulate immunecheckpoints such as 2B4, 4-1BB (CD137), AaR, B7-H3, B7-H4, BAFFR, BTLA,CD2, CD7, CD27, CD28, CD30, CD40, CD80, CD83 ligand, CD86, CD160, CD200,CDS, CEACAM, CTLA-4, GITR, HVEM, ICAM-1, KIR, LAG-3, LAIR1, LFA-1(CD11a/CD18), LIGHT, NKG2C, NKp80, OX40, PD-1, PD-L1, PD-L2, SLAMF7,TGFRβ, TIGIT, Tim3 and VISTA. Immuno-oncology agents may be in the formof antibodies, peptides, small molecules or viruses.

In some embodiments, the conjointly administered chemotherapeutic agentis an immuno-oncology therapeutic agent, such as an inhibitor ofarginase, CTLA-4, indoleamine 2,3-dioxygenase, and/or PD-1/PD-L1. Incertain embodiments, the immuno-oncology therapeutic agent isabagovomab, adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox,apolizumab, atezolizumab, avelumab, blinatumomab, BMS-936559,catumaxomab, durvalumab, epacadostat, epratuzumab, indoximod, inotuzumabozogamicin, intelumumab, ipilimumab, isatuximab, lambrolizumab,MED14736, MPDL3280A, nivolumab, ocaratuzumab, ofatumumab, olatatumab,pembrolizumab, pidilizumab, rituximab, ticilimumab, samalizumab, ortremelimumab. Alternatively, the immuno-oncology therapeutic agent isabagovomab, adecatumumab, afutuzumab, anatumomab mafenatox, apolizumab,atezolizumab, blinatumomab, catumaxomab, durvalumab, epacadostat,epratuzumab, indoximod, inotuzumab ozogamicin, intelumumab, ipilimumab,isatuximab, lambrolizumab, nivolumab, ocaratuzumab, olatatumab,pembrolizumab, pidilizumab, ticilimumab, samalizumab, or tremelimumab.

Exemplary immuno-oncology agents are disclosed in Adams, J. L. et al.“Big Opportunities for Small Molecules in Immuno-Oncology” NatureReviews Drug Discovery 2015, 14, page 603-621, the contents of which arehereby incorporated by reference.

In certain embodiments, the conjointly administered chemotherapeuticagent is a pro-inflammatory agent. In certain embodiments, thepro-inflammatory agent administered with the bis-THIQs of the inventionis a cytokine or a chemokine.

Pro-inflammatory cytokines are produced predominantly by activatedmacrophages and are involved in the up-regulation of inflammatoryreactions. Exemplary pro-inflammatory cytokines include IL-1, IL-1β,IL-6, IL-8, TNF-α, and IFN-γ.

Chemokines are a group of small cytokines. Pro-inflammatory chemokinespromote recruitment and activation of multiple lineages of leukocytes(e.g., lymphocytes, macrophages). Chemokines are related in primarystructure and share several conserved amino acid residues. Inparticular, chemokines typically include two or four cysteine residuesthat contribute to the three-dimensional structure via formation ofdisulfide bonds. Chemokines may be classified in one of four groups: C—Cchemokines, C—X—C chemokines, C chemokines, and C—X₃—C chemokines. C—X—Cchemokines include a number of potent chemoattractants and activators ofneutrophils, such as interleukin 8 (IL-8), PF4 and neutrophil-activatingpeptide-2 (NAP-2). The C—C chemokines include, for example, RANTES(Regulated on Activation, Normal T Expressed and Secreted), macrophageinflammatory proteins 1-alpha and 1-beta (MIP-1α and MIP-1β), eotaxinand human monocyte chemotactic proteins 1 to 3 (MCP-1, MCP-2, MCP-3),which have been characterized as chemoattractants and activators ofmonocytes or lymphocytes. Accordingly, exemplary pro-inflammatorychemokines include MIP-1α, MIP-1β, MCP-1, MCP-2, MCP-3, IL-8, PF4,NAP-2, RANTES, CCL2, CCL3, CCL4, CCL5, CCL11, CXCL2, CXCL8, and CXCL10.

In certain embodiments, the method of treating or preventing cancerfurther comprises administering one or more non-chemical methods ofcancer treatment, such as radiation therapy, surgery, thermoablation,focused ultrasound therapy, cryotherapy, or a combination of theforegoing.

In certain embodiments of the invention, the chemotherapeutic agent isadministered simultaneously with the bis-THIQ. In certain embodiments,the chemotherapeutic agent is administered within about 5 minutes towithin about 168 hours prior or after of the bis-THIQ.

In certain embodiments, the step of administering comprises oraladministration of the therapeutic agent. Alternatively, the step ofadministering can comprise parenteral administration of the therapeuticagent. Further methods of administration are discussed herein.

In certain embodiments, the subject is a human.

In certain embodiments, the therapeutic agent is a compound of FormulaV, VA, VB, VI, VIA, or VIB. Exemplary compounds are described herein.

The present invention also provides a method for treating or preventingcancer, comprising conjointly administering to a subject in need thereofa therapeutically effective amount of a compound of Formula V, VA, VB,VI, VIA, or VIB and one or more additional chemotherapeutic agents.

In certain embodiments, the combination therapy regimen is moreefficacious than a therapy regimen of the bis-THIQ agent (e.g., acompound of Formula V, VA, VB, VI, VIA, or VIB) as a single agent, or atherapy regimen of the additional chemotherapeutic agent as a singleagent.

Definitions

The term “acyl” is art-recognized and refers to a group represented bythe general formula hydrocarbylC(O)—, preferably alkylC(O)—.

The term “acylamino” is art-recognized and refers to an amino groupsubstituted with an acyl group and may be represented, for example, bythe formula hydrocarbylC(O)NH—.

The term “acyloxy” is art-recognized and refers to a group representedby the general formula hydrocarbylC(O)O—, preferably alkylC(O)O—.

The term “alkoxy” refers to an alkyl group, preferably a lower alkylgroup, having an oxygen attached thereto. Representative alkoxy groupsinclude methoxy, ethoxy, propoxy, tert-butoxy and the like.

The term “alkoxyalkyl” refers to an alkyl group substituted with analkoxy group and may be represented by the general formulaalkyl-O-alkyl.

The term “alkenyl”, as used herein, refers to an aliphatic groupcontaining at least one double bond and is intended to include both“unsubstituted alkenyls” and “substituted alkenyls”, the latter of whichrefers to alkenyl moieties having substituents replacing a hydrogen onone or more carbons of the alkenyl group. Such substituents may occur onone or more carbons that are included or not included in one or moredouble bonds. Moreover, such substituents include all those contemplatedfor alkyl groups, as discussed below, except where stability isprohibitive. For example, substitution of alkenyl groups by one or morealkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups iscontemplated.

An “alkyl” group or “alkane” is a straight chained or branchednon-aromatic hydrocarbon which is completely saturated. Typically, astraight chained or branched alkyl group has from 1 to about 20 carbonatoms, preferably from 1 to about 10 unless otherwise defined. Examplesof straight chained and branched alkyl groups include methyl, ethyl,n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl,pentyl and octyl. A C₁-C₆ straight chained or branched alkyl group isalso referred to as a “lower alkyl” group.

Moreover, the term “alkyl” (or “lower alkyl”) as used throughout thespecification, examples, and claims is intended to include both“unsubstituted alkyls” and “substituted alkyls”, the latter of whichrefers to alkyl moieties having substituents replacing one or morehydrogens on one or more carbons of the hydrocarbon backbone. Suchsubstituents, if not otherwise specified, can include, for example, ahalogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl,a formyl, or an acyl), a thiocarbonyl (such as a thioester, athioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, aphosphonate, a phosphinate, an amino, an amido, an amidine, an imine, acyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, asulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, anaralkyl, a guanidino, or an aromatic or heteroaromatic moiety. It willbe understood by those skilled in the art that the moieties substitutedon the hydrocarbon chain can themselves be substituted, if appropriate.For instance, the substituents of a substituted alkyl may includesubstituted and unsubstituted forms of amino, azido, imino, amido,phosphoryl (including phosphonate and phosphinate), sulfonyl (includingsulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, aswell as ethers, alkylthios, carbonyls (including ketones, aldehydes,carboxylates, and esters), —CF₃, —CN and the like. Exemplary substitutedalkyls are described below. Cycloalkyls can be further substituted withalkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl-substitutedalkyls, —CF₃, —CN, and the like.

The term “C_(x-y)” when used in conjunction with a chemical moiety, suchas, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant toinclude groups that contain from x to y carbons in the chain. Forexample, the term “C_(x-y)alkyl” refers to substituted or unsubstitutedsaturated hydrocarbon groups, including straight-chain alkyl andbranched-chain alkyl groups that contain from x to y carbons in thechain, including haloalkyl groups such as trifluoromethyl and2,2,2-trifluoroethyl, etc. C₀ alkyl indicates a hydrogen where the groupis in a terminal position, a bond if internal. The terms“C_(2-y)alkenyl” and “C_(2-y)alkynyl” refer to substituted orunsubstituted unsaturated aliphatic groups analogous in length andpossible substitution to the alkyls described above, but that contain atleast one double or triple bond respectively.

The term “alkylamino”, as used herein, refers to an amino groupsubstituted with at least one alkyl group.

The term “alkylthio”, as used herein, refers to a thiol groupsubstituted with an alkyl group and may be represented by the generalformula alkylS—.

The term “alkynyl”, as used herein, refers to an aliphatic groupcontaining at least one triple bond and is intended to include both“unsubstituted alkynyls” and “substituted alkynyls”, the latter of whichrefers to alkynyl moieties having substituents replacing a hydrogen onone or more carbons of the alkynyl group. Such substituents may occur onone or more carbons that are included or not included in one or moretriple bonds. Moreover, such substituents include all those contemplatedfor alkyl groups, as discussed above, except where stability isprohibitive. For example, substitution of alkynyl groups by one or morealkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups iscontemplated.

The term “amide”, as used herein, refers to a group

wherein each R¹⁰ independently represent a hydrogen or hydrocarbylgroup, or two R¹⁰ are taken together with the N atom to which they areattached complete a heterocycle having from 4 to 8 atoms in the ringstructure.

The terms “amine” and “amino” are art-recognized and refer to bothunsubstituted and substituted amines and salts thereof, e.g., a moietythat can be represented by

wherein each R¹⁰ independently represents a hydrogen or a hydrocarbylgroup, or two R¹¹ are taken together with the N atom to which they areattached complete a heterocycle having from 4 to 8 atoms in the ringstructure.

The term “aminoalkyl”, as used herein, refers to an alkyl groupsubstituted with an amino group.

The term “aralkyl”, as used herein, refers to an alkyl group substitutedwith an aryl group.

The term “aryl” as used herein include substituted or unsubstitutedsingle-ring aromatic groups in which each atom of the ring is carbon.Preferably the ring is a 5- to 7-membered ring, more preferably a6-membered ring. The term “aryl” also includes polycyclic ring systemshaving two or more cyclic rings in which two or more carbons are commonto two adjoining rings wherein at least one of the rings is aromatic,e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls,cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Aryl groupsinclude benzene, naphthalene, phenanthrene, phenol, aniline, and thelike.

The term “carbamate” is art-recognized and refers to a group

wherein R⁹ and R¹⁰ independently represent hydrogen or a hydrocarbylgroup, such as an alkyl group, or R⁹ and R¹⁰ taken together with theintervening atom(s) complete a heterocycle having from 4 to 8 atoms inthe ring structure.

The terms “carbocycle”, and “carbocyclic”, as used herein, refers to asaturated or unsaturated ring in which each atom of the ring is carbon.The term carbocycle includes both aromatic carbocycles and non-aromaticcarbocycles. Non-aromatic carbocycles include both cycloalkane rings, inwhich all carbon atoms are saturated, and cycloalkene rings, whichcontain at least one double bond. “Carbocycle” includes 5-7 memberedmonocyclic and 8-12 membered bicyclic rings. Each ring of a bicycliccarbocycle may be selected from saturated, unsaturated and aromaticrings. Carbocycle includes bicyclic molecules in which one, two or threeor more atoms are shared between the two rings. The term “fusedcarbocycle” refers to a bicyclic carbocycle in which each of the ringsshares two adjacent atoms with the other ring. Each ring of a fusedcarbocycle may be selected from saturated, unsaturated and aromaticrings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, maybe fused to a saturated or unsaturated ring, e.g., cyclohexane,cyclopentane, or cyclohexene. Any combination of saturated, unsaturatedand aromatic bicyclic rings, as valence permits, is included in thedefinition of carbocyclic. Exemplary “carbocycles” include cyclopentane,cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene,1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene andadamantane. Exemplary fused carbocycles include decalin, naphthalene,1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane,4,5,6,7-tetrahydro-1H-indene and bicyclo[4.1.0]hept-3-ene. “Carbocycles”may be susbstituted at any one or more positions capable of bearing ahydrogen atom.

A “cycloalkyl” group is a cyclic hydrocarbon which is completelysaturated. “Cycloalkyl” includes monocyclic and bicyclic rings.Typically, a monocyclic cycloalkyl group has from 3 to about 10 carbonatoms, more typically 3 to 8 carbon atoms unless otherwise defined. Thesecond ring of a bicyclic cycloalkyl may be selected from saturated,unsaturated and aromatic rings. Cycloalkyl includes bicyclic moleculesin which one, two or three or more atoms are shared between the tworings. The term “fused cycloalkyl” refers to a bicyclic cycloalkyl inwhich each of the rings shares two adjacent atoms with the other ring.The second ring of a fused bicyclic cycloalkyl may be selected fromsaturated, unsaturated and aromatic rings. A “cycloalkenyl” group is acyclic hydrocarbon containing one or more double bonds.

The term “(cycloalkyl)alkyl”, as used herein, refers to an alkyl groupsubstituted with a cycloalkyl group.

The term “carbonate” is art-recognized and refers to a group —OCO₂—R¹⁰,wherein R¹⁰ represents a hydrocarbyl group.

The term “carboxy”, as used herein, refers to a group represented by theformula —CO₂H.

The term “ester”, as used herein, refers to a group —C(O)OR¹⁰ whereinR¹⁰ represents a hydrocarbyl group.

The term “ether”, as used herein, refers to a hydrocarbyl group linkedthrough an oxygen to another hydrocarbyl group. Accordingly, an ethersubstituent of a hydrocarbyl group may be hydrocarbyl-O—. Ethers may beeither symmetrical or unsymmetrical. Examples of ethers include, but arenot limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethersinclude “alkoxyalkyl” groups, which may be represented by the generalformula alkyl-O-alkyl.

The terms “halo” and “halogen” as used herein means halogen and includeschloro, fluoro, bromo, and iodo.

The term “heteroaralkyl”, as used herein, refers to an alkyl groupsubstituted with a heteroaryl group.

The term “heteroalkyl”, as used herein, refers to a saturated orunsaturated chain of carbon atoms and at least one heteroatom, whereinno two heteroatoms are adjacent.

The term “heteroaryl” includes substituted or unsubstituted aromaticsingle ring structures, preferably 5- to 7-membered rings, morepreferably 5- to 6-membered rings, whose ring structures include atleast one heteroatom, preferably one to four heteroatoms, morepreferably one or two heteroatoms. The terms “heteroaryl” also includepolycyclic ring systems having two or more cyclic rings in which two ormore carbons are common to two adjoining rings wherein at least one ofthe rings is heteroaromatic, e.g., the other cyclic rings can becycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/orheterocyclyls. Heteroaryl groups include, for example, pyrrole, furan,thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine,pyridazine, and pyrimidine, and the like.

The term “heteroatom” as used herein means an atom of any element otherthan carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, andsulfur.

The terms “heterocycloalkyl”, “heterocycle”, and “heterocyclic” refer tosubstituted or unsubstituted non-aromatic ring structures, preferably 3-to 10-membered rings, more preferably 3- to 7-membered rings, whose ringstructures include at least one heteroatom, preferably one to fourheteroatoms, more preferably one or two heteroatoms. The terms“heterocycloalkyl” and “heterocyclic” also include polycyclic ringsystems having two or more cyclic rings in which two or more carbons arecommon to two adjoining rings wherein at least one of the rings isheterocyclic, e.g., the other cyclic rings can be cycloalkyls,cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.Heterocycloalkyl groups include, for example, piperidine, piperazine,pyrrolidine, morpholine, lactones, lactams, and the like.

The term “(heterocycloalkyl)alkyl”, as used herein, refers to an alkylgroup substituted with a heterocycloalkyl group.

The term “hydrocarbyl”, as used herein, refers to a group that is bondedthrough a carbon atom that does not have a ═O or ═S substituent, andtypically has at least one carbon-hydrogen bond and a primarily carbonbackbone, but may optionally include heteroatoms. Thus, groups likemethyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered to behydrocarbyl for the purposes of this application, but substituents suchas acetyl (which has a ═O substituent on the linking carbon) and ethoxy(which is linked through oxygen, not carbon) are not. Hydrocarbyl groupsinclude, but are not limited to aryl, heteroaryl, carbocycle,heterocyclyl, alkyl, alkenyl, alkynyl, and combinations thereof.

The term “hydroxyalkyl”, as used herein, refers to an alkyl groupsubstituted with a hydroxy group.

The term “lower” when used in conjunction with a chemical moiety, suchas, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant toinclude groups where there are ten or fewer non-hydrogen atoms in thesubstituent, preferably six or fewer. A “lower alkyl”, for example,refers to an alkyl group that contains ten or fewer carbon atoms,preferably six or fewer. In certain embodiments, acyl, acyloxy, alkyl,alkenyl, alkynyl, or alkoxy substituents defined herein are respectivelylower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, orlower alkoxy, whether they appear alone or in combination with othersubstituents, such as in the recitations hydroxyalkyl and aralkyl (inwhich case, for example, the atoms within the aryl group are not countedwhen counting the carbon atoms in the alkyl substituent).

The terms “polycyclyl”, “polycycle”, and “polycyclic” refer to two ormore rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls,heteroaryls, and/or heterocyclyls) in which two or more atoms are commonto two adjoining rings, e.g., the rings are “fused rings”. Each of therings of the polycycle can be substituted or unsubstituted. In certainembodiments, each ring of the polycycle contains from 3 to 10 atoms inthe ring, preferably from 5 to 7.

The term “silyl” refers to a silicon moiety with three hydrocarbylmoieties attached thereto.

The term “substituted” refers to moieties having substituents replacinga hydrogen on one or more carbons of the backbone. It will be understoodthat “substitution” or “substituted with” includes the implicit provisothat such substitution is in accordance with permitted valence of thesubstituted atom and the substituent, and that the substitution resultsin a stable compound, e.g., which does not spontaneously undergotransformation such as by rearrangement, cyclization, elimination, etc.As used herein, the term “substituted” is contemplated to include allpermissible substituents of organic compounds. In a broad aspect, thepermissible substituents include acyclic and cyclic, branched andunbranched, carbocyclic and heterocyclic, aromatic and non-aromaticsubstituents of organic compounds. The permissible substituents can beone or more and the same or different for appropriate organic compounds.For purposes of this invention, the heteroatoms such as nitrogen mayhave hydrogen substituents and/or any permissible substituents oforganic compounds described herein which satisfy the valences of theheteroatoms. Substituents can include any substituents described herein,for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, analkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as athioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, aphosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine,an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, asulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, aheterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. Itwill be understood by those skilled in the art that substituents canthemselves be substituted, if appropriate. Unless specifically stated as“unsubstituted,” references to chemical moieties herein are understoodto include substituted variants. For example, reference to an “aryl”group or moiety implicitly includes both substituted and unsubstitutedvariants.

The term “sulfate” is art-recognized and refers to the group —OSO₃H, ora pharmaceutically acceptable salt thereof.

The term “sulfonamide” is art-recognized and refers to the grouprepresented by the general formulae

wherein R⁹ and R¹⁰ independently represents hydrogen or hydrocarbyl,such as alkyl, or R⁹ and R¹⁰ taken together with the intervening atom(s)complete a heterocycle having from 4 to 8 atoms in the ring structure.

The term “sulfoxide” is art-recognized and refers to the group—S(O)—R¹⁰, wherein R¹⁰ represents a hydrocarbyl.

The term “sulfonate” is art-recognized and refers to the group SO₃H, ora pharmaceutically acceptable salt thereof.

The term “sulfone” is art-recognized and refers to the group —S(O)₂—R¹⁰,wherein R¹⁰ represents a hydrocarbyl.

The term “thioalkyl”, as used herein, refers to an alkyl groupsubstituted with a thiol group.

The term “thioester”, as used herein, refers to a group —C(O)SR¹⁰ or—SC(O)R¹⁰ wherein R¹⁰ represents a hydrocarbyl.

The term “thioether”, as used herein, is equivalent to an ether, whereinthe oxygen is replaced with a sulfur.

The term “urea” is art-recognized and may be represented by the generalformula

wherein R⁹ and R¹⁰ independently represent hydrogen or a hydrocarbyl,such as alkyl, or either occurrence of R⁹ taken together with R¹⁰ andthe intervening atom(s) complete a heterocycle having from 4 to 8 atomsin the ring structure.

“Protecting group” refers to a group of atoms that, when attached to areactive functional group in a molecule, mask, reduce or prevent thereactivity of the functional group. Typically, a protecting group may beselectively removed as desired during the course of a synthesis.Examples of protecting groups can be found in Greene and Wuts,Protective Groups in Organic Chemistry, 3^(rd) Ed., 1999, John Wiley &Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods,Vols. 1-8, 1971-1996, John Wiley & Sons, NY. Representative nitrogenprotecting groups include, but are not limited to, formyl, acetyl,trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl(“Boc”), trimethylsilyl (“TMS”), 2-trimethylsilyl-ethanesulfonyl(“TES”), trityl and substituted trityl groups, allyloxycarbonyl,9-fluorenylmethyloxycarbonyl (“FMOC”), nitro-veratryloxycarbonyl(“NVOC”) and the like. Representative hydroxyl protecting groupsinclude, but are not limited to, those where the hydroxyl group iseither acylated (esterified) or alkylated such as benzyl and tritylethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilylethers (e.g., TMS or TIPS groups), glycol ethers, such as ethyleneglycol and propylene glycol derivatives and allyl ethers.

As used herein, a therapeutic that “prevents” a disorder or conditionrefers to a compound that, in a statistical sample, reduces theoccurrence of the disorder or condition in the treated sample relativeto an untreated control sample, or delays the onset or reduces theseverity of one or more symptoms of the disorder or condition relativeto the untreated control sample.

The term “treating” includes prophylactic and/or therapeutic treatments.The term “prophylactic or therapeutic” treatment is art-recognized andincludes administration to the host of one or more of the subjectcompositions. If it is administered prior to clinical manifestation ofthe unwanted condition (e.g., disease or other unwanted state of thehost animal) then the treatment is prophylactic (i.e., it protects thehost against developing the unwanted condition), whereas if it isadministered after manifestation of the unwanted condition, thetreatment is therapeutic, (i.e., it is intended to diminish, ameliorate,or stabilize the existing unwanted condition or side effects thereof).

The term “prodrug” is intended to encompass compounds which, underphysiologic conditions, are converted into the therapeutically activeagents of the present invention (e.g., a compound of Formula V, VA, VB,VI, VIA, or VIB). A common method for making a prodrug is to include oneor more selected moieties which are hydrolyzed under physiologicconditions to reveal the desired molecule. In other embodiments, theprodrug is converted by an enzymatic activity of the host animal. Forexample, esters or carbonates (e.g., esters or carbonates of alcohols orcarboxylic acids) are preferred prodrugs of the present invention.Alternatively, amides (e.g., an amide of an amino group) may be aprodrug of the invention. In certain embodiments, some or all of theactive compounds in a formulation represented above can be replaced withthe corresponding suitable prodrug, e.g., wherein a hydroxyl in theparent compound is presented as an ester or a carbonate or carboxylicacid present in the parent compound is presented as an ester.

Pharmaceutical Compositions

In certain embodiments, the invention provides a pharmaceuticalcomposition comprising a compound of the invention (e.g., a compound ofFormula V, VA, VB, VI, VIA, or VIB), or a pharmaceutically acceptablesalt thereof; and a pharmaceutically acceptable carrier.

In certain embodiments, the present invention provides a pharmaceuticalpreparation suitable for use in a human patient, comprising any compoundof the invention (e.g., a compound of Formula V, VA, VB, VI, VIA, orVIB), and one or more pharmaceutically acceptable excipients. In certainembodiments, the pharmaceutical preparations may be for use in treatingor preventing a condition or disease as described herein. In certainembodiments, the pharmaceutical preparations have a low enough pyrogenactivity to be suitable for use in a human patient.

One embodiment of the present invention provides a pharmaceutical kitcomprising a compound of the invention (e.g., a compound of Formula V,VA, VB, VI, VIA, or VIB), or a pharmaceutically acceptable salt thereof,and optionally directions on how to administer the compound.

The compositions and methods of the present invention may be utilized totreat an individual in need thereof. In certain embodiments, theindividual is a mammal such as a human, or a non-human mammal. Whenadministered to an animal, such as a human, the composition or thecompound is preferably administered as a pharmaceutical compositioncomprising, for example, a compound of the invention and apharmaceutically acceptable carrier. Pharmaceutically acceptablecarriers are well known in the art and include, for example, aqueoussolutions such as water or physiologically buffered saline or othersolvents or vehicles such as glycols, glycerol, oils such as olive oil,or injectable organic esters. In certain preferred embodiments, whensuch pharmaceutical compositions are for human administration,particularly for invasive routes of administration (i.e., routes, suchas injection or implantation, that circumvent transport or diffusionthrough an epithelial barrier), the aqueous solution is pyrogen-free, orsubstantially pyrogen-free. The excipients can be chosen, for example,to effect delayed release of an agent or to selectively target one ormore cells, tissues or organs. The pharmaceutical composition can be indosage unit form such as tablet, capsule (including sprinkle capsule andgelatin capsule), granule, lyophile for reconstitution, powder,solution, syrup, suppository, injection or the like. The composition canalso be present in a transdermal delivery system, e.g., a skin patch.The composition can also be present in a solution suitable for topicaladministration, such as an eye drop.

A pharmaceutically acceptable carrier can contain physiologicallyacceptable agents that act, for example, to stabilize, increasesolubility or to increase the absorption of a compound such as acompound of the invention. Such physiologically acceptable agentsinclude, for example, carbohydrates, such as glucose, sucrose ordextrans, antioxidants, such as ascorbic acid or glutathione, chelatingagents, low molecular weight proteins or other stabilizers orexcipients. The choice of a pharmaceutically acceptable carrier,including a physiologically acceptable agent, depends, for example, onthe route of administration of the composition. The preparation orpharmaceutical composition can be a selfemulsifying drug delivery systemor a selfmicroemulsifying drug delivery system. The pharmaceuticalcomposition (preparation) also can be a liposome or other polymermatrix, which can have incorporated therein, for example, a compound ofthe invention. Liposomes, for example, which comprise phospholipids orother lipids, are nontoxic, physiologically acceptable and metabolizablecarriers that are relatively simple to make and administer.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The phrase “pharmaceutically acceptable carrier” as used herein means apharmaceutically acceptable material, composition or vehicle, such as aliquid or solid filler, diluent, excipient, solvent or encapsulatingmaterial. Each carrier must be “acceptable” in the sense of beingcompatible with the other ingredients of the formulation and notinjurious to the patient. Some examples of materials which can serve aspharmaceutically acceptable carriers include: (1) sugars, such aslactose, glucose and sucrose; (2) starches, such as corn starch andpotato starch; (3) cellulose, and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4)powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients,such as cocoa butter and suppository waxes; (9) oils, such as peanutoil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; (10) glycols, such as propylene glycol; (11) polyols, suchas glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters,such as ethyl oleate and ethyl laurate; (13) agar; (14) bufferingagents, such as magnesium hydroxide and aluminum hydroxide; (15) alginicacid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer'ssolution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21)other non-toxic compatible substances employed in pharmaceuticalformulations.

A pharmaceutical composition (preparation) can be administered to asubject by any of a number of routes of administration including, forexample, orally (for example, drenches as in aqueous or non-aqueoussolutions or suspensions, tablets, capsules (including sprinkle capsulesand gelatin capsules), boluses, powders, granules, pastes forapplication to the tongue); absorption through the oral mucosa (e.g.,sublingually); anally, rectally or vaginally (for example, as a pessary,cream or foam); parenterally (including intramuscularly, intravenously,subcutaneously or intrathecally as, for example, a sterile solution orsuspension); nasally; intraperitoneally; subcutaneously; transdermally(for example as a patch applied to the skin); and topically (forexample, as a cream, ointment or spray applied to the skin, or as an eyedrop). The compound may also be formulated for inhalation. In certainembodiments, a compound may be simply dissolved or suspended in sterilewater. Details of appropriate routes of administration and compositionssuitable for same can be found in, for example, U.S. Pat. Nos.6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and4,172,896, as well as in patents cited therein.

The formulations may conveniently be presented in unit dosage form andmay be prepared by any methods well known in the art of pharmacy. Theamount of active ingredient which can be combined with a carriermaterial to produce a single dosage form will vary depending upon thehost being treated, the particular mode of administration. The amount ofactive ingredient that can be combined with a carrier material toproduce a single dosage form will generally be that amount of thecompound which produces a therapeutic effect. Generally, out of onehundred percent, this amount will range from about 1 percent to aboutninety-nine percent of active ingredient, preferably from about 5percent to about 70 percent, most preferably from about 10 percent toabout 30 percent.

Methods of preparing these formulations or compositions include the stepof bringing into association an active compound, such as a compound ofthe invention, with the carrier and, optionally, one or more accessoryingredients. In general, the formulations are prepared by uniformly andintimately bringing into association a compound of the present inventionwith liquid carriers, or finely divided solid carriers, or both, andthen, if necessary, shaping the product.

Formulations of the invention suitable for oral administration may be inthe form of capsules (including sprinkle capsules and gelatin capsules),cachets, pills, tablets, lozenges (using a flavored basis, usuallysucrose and acacia or tragacanth), lyophile, powders, granules, or as asolution or a suspension in an aqueous or non-aqueous liquid, or as anoil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup,or as pastilles (using an inert base, such as gelatin and glycerin, orsucrose and acacia) and/or as mouth washes and the like, each containinga predetermined amount of a compound of the present invention as anactive ingredient. Compositions or compounds may also be administered asa bolus, electuary or paste.

To prepare solid dosage forms for oral administration (capsules(including sprinkle capsules and gelatin capsules), tablets, pills,dragees, powders, granules and the like), the active ingredient is mixedwith one or more pharmaceutically acceptable carriers, such as sodiumcitrate or dicalcium phosphate, and/or any of the following: (1) fillersor extenders, such as starches, lactose, sucrose, glucose, mannitol,and/or silicic acid; (2) binders, such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone,sucrose and/or acacia; (3) humectants, such as glycerol; (4)disintegrating agents, such as agar-agar, calcium carbonate, potato ortapioca starch, alginic acid, certain silicates, and sodium carbonate;(5) solution retarding agents, such as paraffin; (6) absorptionaccelerators, such as quaternary ammonium compounds; (7) wetting agents,such as, for example, cetyl alcohol and glycerol monostearate; (8)absorbents, such as kaolin and bentonite clay; (9) lubricants, such atalc, calcium stearate, magnesium stearate, solid polyethylene glycols,sodium lauryl sulfate, and mixtures thereof; (10) complexing agents,such as, modified and unmodified cyclodextrins; and (11) coloringagents. In the case of capsules (including sprinkle capsules and gelatincapsules), tablets and pills, the pharmaceutical compositions may alsocomprise buffering agents. Solid compositions of a similar type may alsobe employed as fillers in soft and hard-filled gelatin capsules usingsuch excipients as lactose or milk sugars, as well as high molecularweight polyethylene glycols and the like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

The tablets, and other solid dosage forms of the pharmaceuticalcompositions, such as dragees, capsules (including sprinkle capsules andgelatin capsules), pills and granules, may optionally be scored orprepared with coatings and shells, such as enteric coatings and othercoatings well known in the pharmaceutical-formulating art. They may alsobe formulated so as to provide slow or controlled release of the activeingredient therein using, for example, hydroxypropylmethyl cellulose invarying proportions to provide the desired release profile, otherpolymer matrices, liposomes and/or microspheres. They may be sterilizedby, for example, filtration through a bacteria-retaining filter, or byincorporating sterilizing agents in the form of sterile solidcompositions that can be dissolved in sterile water, or some othersterile injectable medium immediately before use. These compositions mayalso optionally contain opacifying agents and may be of a compositionthat they release the active ingredient(s) only, or preferentially, in acertain portion of the gastrointestinal tract, optionally, in a delayedmanner. Examples of embedding compositions that can be used includepolymeric substances and waxes. The active ingredient can also be inmicro-encapsulated form, if appropriate, with one or more of theabove-described excipients.

Liquid dosage forms useful for oral administration includepharmaceutically acceptable emulsions, lyophiles for reconstitution,microemulsions, solutions, suspensions, syrups and elixirs. In additionto the active ingredient, the liquid dosage forms may contain inertdiluents commonly used in the art, such as, for example, water or othersolvents, cyclodextrins and derivatives thereof, solubilizing agents andemulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate,ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol,1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn,germ (e.g., wheat germ), olive, castor and sesame oils), glycerol,tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters ofsorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, and mixturesthereof.

Formulations of the pharmaceutical compositions for rectal, vaginal, orurethral administration may be presented as a suppository, which may beprepared by mixing one or more active compounds with one or moresuitable nonirritating excipients or carriers comprising, for example,cocoa butter, polyethylene glycol, a suppository wax or a salicylate,and which is solid at room temperature, but liquid at body temperatureand, therefore, will melt in the rectum or vaginal cavity and releasethe active compound.

Formulations of the pharmaceutical compositions for administration tothe mouth may be presented as a mouthwash, or an oral spray, or an oralointment.

Alternatively or additionally, compositions can be formulated fordelivery via a catheter, stent, wire, or other intraluminal device.Delivery via such devices may be especially useful for delivery to thebladder, urethra, ureter, rectum, or intestine.

Formulations which are suitable for vaginal administration also includepessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining such carriers as are known in the art to be appropriate.

Dosage forms for the topical or transdermal administration includepowders, sprays, ointments, pastes, creams, lotions, gels, solutions,patches and inhalants. The active compound may be mixed under sterileconditions with a pharmaceutically acceptable carrier, and with anypreservatives, buffers, or propellants that may be required.

The ointments, pastes, creams and gels may contain, in addition to anactive compound, excipients, such as animal and vegetable fats, oils,waxes, paraffins, starch, tragacanth, cellulose derivatives,polyethylene glycols, silicones, bentonites, silicic acid, talc and zincoxide, or mixtures thereof.

Powders and sprays can contain, in addition to an active compound,excipients such as lactose, talc, silicic acid, aluminum hydroxide,calcium silicates and polyamide powder, or mixtures of these substances.Sprays can additionally contain customary propellants, such aschlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, suchas butane and propane.

Transdermal patches have the added advantage of providing controlleddelivery of a compound of the present invention to the body. Such dosageforms can be made by dissolving or dispersing the active compound in theproper medium. Absorption enhancers can also be used to increase theflux of the compound across the skin. The rate of such flux can becontrolled by either providing a rate controlling membrane or dispersingthe compound in a polymer matrix or gel.

Ophthalmic formulations, eye ointments, powders, solutions and the like,are also contemplated as being within the scope of this invention.Exemplary ophthalmic formulations are described in U.S. Publication Nos.2005/0080056, 2005/0059744, 2005/0031697 and 2005/004074 and U.S. Pat.No. 6,583,124, the contents of which are incorporated herein byreference. If desired, liquid ophthalmic formulations have propertiessimilar to that of lacrimal fluids, aqueous humor or vitreous humor orare compatable with such fluids. A preferred route of administration islocal administration (e.g., topical administration, such as eye drops,or administration via an implant).

The phrases “parenteral administration” and “administered parenterally”as used herein means modes of administration other than enteral andtopical administration, usually by injection, and includes, withoutlimitation, intravenous, intramuscular, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular,subarachnoid, intraspinal and intrasternal injection and infusion.Pharmaceutical compositions suitable for parenteral administrationcomprise one or more active compounds in combination with one or morepharmaceutically acceptable sterile isotonic aqueous or nonaqueoussolutions, dispersions, suspensions or emulsions, or sterile powderswhich may be reconstituted into sterile injectable solutions ordispersions just prior to use, which may contain antioxidants, buffers,bacteriostats, solutes which render the formulation isotonic with theblood of the intended recipient or suspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers that may beemployed in the pharmaceutical compositions of the invention includewater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol, and the like), and suitable mixtures thereof,vegetable oils, such as olive oil, and injectable organic esters, suchas ethyl oleate. Proper fluidity can be maintained, for example, by theuse of coating materials, such as lecithin, by the maintenance of therequired particle size in the case of dispersions, and by the use ofsurfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms may be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, and the like. It may also bedesirable to include isotonic agents, such as sugars, sodium chloride,and the like into the compositions. In addition, prolonged absorption ofthe injectable pharmaceutical form may be brought about by the inclusionof agents that delay absorption such as aluminum monostearate andgelatin.

In some cases, in order to prolong the effect of a drug, it is desirableto slow the absorption of the drug from subcutaneous or intramuscularinjection. This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material having poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolution,which, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Injectable depot forms are made by forming microencapsulated matrices ofthe subject compounds in biodegradable polymers such aspolylactide-polyglycolide. Depending on the ratio of drug to polymer,and the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions that are compatible with body tissue.

For use in the methods of this invention, active compounds can be givenper se or as a pharmaceutical composition containing, for example, 0.1to 99.5% (more preferably, 0.5 to 90%) of active ingredient incombination with a pharmaceutically acceptable carrier.

Methods of introduction may also be provided by rechargeable orbiodegradable devices. Various slow release polymeric devices have beendeveloped and tested in vivo in recent years for the controlled deliveryof drugs, including proteinacious biopharmaceuticals. A variety ofbiocompatible polymers (including hydrogels), including bothbiodegradable and non-degradable polymers, can be used to form animplant for the sustained release of a compound at a particular targetsite.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions may be varied so as to obtain an amount of the activeingredient that is effective to achieve the desired therapeutic responsefor a particular patient, composition, and mode of administration,without being toxic to the patient.

The selected dosage level will depend upon a variety of factorsincluding the activity of the particular compound or combination ofcompounds employed, or the ester, salt or amide thereof, the route ofadministration, the time of administration, the rate of excretion of theparticular compound(s) being employed, the duration of the treatment,other drugs, compounds and/or materials used in combination with theparticular compound(s) employed, the age, sex, weight, condition,general health and prior medical history of the patient being treated,and like factors well known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the therapeutically effective amount of thepharmaceutical composition required. For example, the physician orveterinarian could start doses of the pharmaceutical composition orcompound at levels lower than that required in order to achieve thedesired therapeutic effect and gradually increase the dosage until thedesired effect is achieved. By “therapeutically effective amount” ismeant the concentration of a compound that is sufficient to elicit thedesired therapeutic effect. It is generally understood that theeffective amount of the compound will vary according to the weight, sex,age, and medical history of the subject. Other factors which influencethe effective amount may include, but are not limited to, the severityof the patient's condition, the disorder being treated, the stability ofthe compound, and, if desired, another type of therapeutic agent beingadministered with the compound of the invention. A larger total dose canbe delivered by multiple administrations of the agent. Methods todetermine efficacy and dosage are known to those skilled in the art(Isselbacher et al. (1996) Harrison's Principles of Internal Medicine 13ed., 1814-1882, herein incorporated by reference).

In general, a suitable daily dose of an active compound used in thecompositions and methods of the invention will be that amount of thecompound that is the lowest dose effective to produce a therapeuticeffect. Such an effective dose will generally depend upon the factorsdescribed above.

If desired, the effective daily dose of the active compound may beadministered as one, two, three, four, five, six or more sub-dosesadministered separately at appropriate intervals throughout the day,optionally, in unit dosage forms. In certain embodiments of the presentinvention, the active compound may be administered two or three timesdaily. In preferred embodiments, the active compound will beadministered once daily.

The patient receiving this treatment is any animal in need, includingprimates, in particular humans, and other mammals such as equines,cattle, swine and sheep; and poultry and pets in general.

In certain embodiments, compounds of the invention may be used alone orconjointly administered with another type of therapeutic agent. As usedherein, the phrase “conjoint administration” refers to any form ofadministration of two or more different therapeutic compounds such thatthe second compound is administered while the previously administeredtherapeutic compound is still effective in the body (e.g., the twocompounds are simultaneously effective in the patient, which may includesynergistic effects of the two compounds). For example, the differenttherapeutic compounds can be administered either in the same formulationor in a separate formulation, either concomitantly or sequentially. Incertain embodiments, the different therapeutic compounds can beadministered within one hour, 12 hours, 24 hours, 36 hours, 48 hours, 72hours, or a week of one another. Thus, an individual who receives suchtreatment can benefit from a combined effect of different therapeuticcompounds.

In certain embodiments, conjoint administration of compounds of theinvention with one or more additional therapeutic agent(s) (e.g., one ormore additional chemotherapeutic agent(s)) provides improved efficacyrelative to each individual administration of the compound of theinvention (e.g., a compound of Formula V, VA, VB, VI, VIA, or VIB) orthe one or more additional therapeutic agent(s). In certain suchembodiments, the conjoint administration provides an additive effect,wherein an additive effect refers to the sum of each of the effects ofindividual administration of the compound of the invention and the oneor more additional therapeutic agent(s).

This invention includes the use of pharmaceutically acceptable salts ofcompounds of the invention in the compositions and methods of thepresent invention. The term “pharmaceutically acceptable salt” as usedherein includes salts derived from inorganic or organic acids including,for example, hydrochloric, hydrobromic, sulfuric, nitric, perchloric,phosphoric, formic, acetic, lactic, maleic, fumaric, succinic, tartaric,glycolic, salicylic, citric, methanesulfonic, benzenesulfonic, benzoic,malonic, trifluoroacetic, trichloroacetic, naphthalene-2-sulfonic,oxalic, mandelic and other acids. Pharmaceutically acceptable salt formscan include forms wherein the ratio of molecules comprising the salt isnot 1:1. For example, the salt may comprise more than one inorganic ororganic acid molecule per molecule of base, such as two hydrochloricacid molecules per molecule of compound of formula V, VA, VB, VI, VIA,or VIB. As another example, the salt may comprise less than oneinorganic or organic acid molecule per molecule of base, such as twomolecules of compound of Formula V, VA, VB, VI, VIA, or VIB per moleculeof tartaric acid.

In further embodiments, contemplated salts of the invention include, butare not limited to, alkyl, dialkyl, trialkyl or tetra-alkyl ammoniumsalts. In certain embodiments, contemplated salts of the inventioninclude, but are not limited to, L-arginine, benenthamine, benzathine,betaine, calcium hydroxide, choline, deanol, diethanolamine,diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine,N-methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine,magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium,1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine,and zinc salts. In certain embodiments, contemplated salts of theinvention include, but are not limited to, Na, Ca, K, Mg, Zn or othermetal salts.

The pharmaceutically acceptable acid addition salts can also exist asvarious solvates, such as with water, methanol, ethanol,dimethylformamide, and the like. Mixtures of such solvates can also beprepared. The source of such solvate can be from the solvent ofcrystallization, inherent in the solvent of preparation orcrystallization, or adventitious to such solvent.

Wetting agents, emulsifiers and lubricants, such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releaseagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the compositions.

Examples of pharmaceutically acceptable antioxidants include: (1)water-soluble antioxidants, such as ascorbic acid, cysteinehydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfiteand the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate,butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT),lecithin, propyl gallate, alpha-tocopherol, and the like; and (3)metal-chelating agents, such as citric acid, ethylenediamine tetraaceticacid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

The invention now being generally described, it will be more readilyunderstood by reference to the following examples which are includedmerely for purposes of illustration of certain aspects and embodimentsof the present invention, and are not intended to limit the invention.

Retrosynthetic Analysis and Synthetic Methodology

To achieve the synthesis of jorumycin and related compounds, theretrosynthetic strategy shown above was developed. As shown, a latestage oxygenation event would provide jorumycin and would greatlysimplify the construction of starting materials, providing pentacycle 6.We then disconnected the central C-ring through cleavage of the lactammoiety in 6, providing bis-THIQ compound 7, which we believed could besynthesized through the enantioselective hydrogenation ofbis-isoquinoline 8. The biaryl nature of 8 naturally suggests that it beformed through a cross-coupling reaction, leading to isoquinolinemonomers 9 and 10. As a key advantage, isoquinolines 9 and 10 could besynthesized through known methods, not limited to those utilizing highlyelectron-rich and it-nucleophilic species. Crucially, this approachwould allow access to the natural products themselves, as well aselectron-rich, -neutral, or -deficient non-natural analogs.

To initiate our synthetic studies we focused our attention on theconstruction of isoquinoline monomer 9. Sonagashira coupling of arylbromide 11, available in two steps from 3,5-dimethoxy-benzaldehyde, withtert-butyldimethylsilyl propargyl alcohol¹² proceeded smoothly; simplyadding solid hydroxylamine hydrochloride to the reaction mixture afterthe coupling provided oxime-bearing alkyne 13 in 85% yield. Catalyticsilver(I) triflate served to activate the alkyne toward nucleophilicattack by the oxime, directly generating isoquinoline N-oxide 9 in 73%yield on up to a 12-gram scale in a single pass.²⁷

Next, we began our synthesis of isoquinoline triflate 10 by usingaryne-based technology developed in our laboratories.²⁸⁻³⁰ Silyl aryltriflate 14, available in 3-steps from 2,3-dimethoxy-toluene, wastreated with cesium fluoride to provide the corresponding aryneintermediate (not shown), which under-went aryne acyl-alkylation with insitu condensation to provide 3-hydroxyisoquinoline 16 in 81% yield.Reaction with trifluo-romethanesulfonic anhydride provides electrophiliccoupling partner 10 in 94% yield.

With working routes to both iso-quinoline monomers in hand, we turnedour attention to the cross-coupling reaction which would be used toconstruct the carbon skeleton of jorumycin. We were pleased to find thatisoquinolines 9 and 10 were efficiently coupled under the conditionsdeveloped by Fagnou and coworkers to provide bis-isoquinoline 18 in 94%yield on a seven gram scale.³¹ This large-scale application of C—Hactivation proceeds through transition state 17 and allows for thedirect construction of 18 without need for prefuctionalization.Importantly, while an excess of N-oxide 9 is required to achieve themaximum efficiency, this appears to be necessary only for kineticreasons, as all excess 9 is recovered after the reaction.

At this stage, we recognized that the Boekelheide rearrangement^(33,34)would be particularly well suited for the advance-ment of our synthesis,utilizing the oxidation already present in the molecule. Prior toimplementing of this rearrange-ment, we oxidized the remaining azineusing methyltrioxorhenium(VII) and hydrogen peroxide³⁵ to providebis-N-oxide 19 in 98% yield with no purification necessary. This speciescan then undergo a double Boekelheide rearrangement in refluxing aceticanhydride, transmuting the N-oxides to the benzylic acetates. Thisprovides triacetoxy compound 20, which undergoes partial hydrolysisunder the reaction conditions to aldehyde 21; subsequent treatment withaqueous lithium hydroxide converges all material to 21 in 34% yield.Oxidation with silver(I) oxide provides the methyl ester, and theaddition of thionyl chloride induces methanolysis of the primary acetateto provide hydro-genation precursor 22 in just three steps.

We were now ready to explore the key hydrogenation event that would formeight new C—H and N—H bonds, including four of the five necessarystereocenters, as well as close the C-ring lactam after fullhydro-genation. While the enantioselective hy-drogenation ofnitrogen-based heterocycles is a well-studied field, isoquinolines areperhaps the most challenging substrates for this transformation.³⁶ Onereason for this is that the products of reduction are highly basic andare known to poison most homogeneous transition metal catalysts. Indeed,to our knowledge only four reports exist which describe enantioselectiveiso-quinoline hydrogenation protocols, only one of which is applicableto 1,3-disub-stituted systems.³⁷⁻⁴⁰

Our stereochemical rationale for this transformation is depicted above.We predicted that the hydroxyl directing group would serve to bothaccelerate the reduction of the B-ring relative to the D-ring (cf. 4)and to serve as a scaffold to direct a chiral catalyst to only a singleface of the aromatic system. Reduction of 1,3-disubstitutedisoquinolines is known to proceed with high syn diastereoselectivity, sowe anticipate the major product after the first two additions ofdihydrogen to be cis-mono-THIQ 23.³⁶⁻⁴⁰ We believed that 23 could act asa bidentate ligand for the metal catalyst, the three-dimensionalstructure of which would direct D-ring hydrogenation from the same face.This form of substrate-reinforced diastereoselectivity predicts theaddition of all four molecules of hydrogen from the same face. Finally,the all-syn nature of 7 places it in close proximity to the amine in theB-ring, and we expected lactamization to be rapid.

Development of Enantioselective Hydrogenation

TABLE 1 Development of Enantioselective Hydrogenation.

entry catalyst loading ligand^(d) temperature yield 23 yield 6^(a)dr^(b) ee 6^(c) 1 [Ir(cod)Cl]₂  5 mol % 26 23° C.  2%  0% ND ND 2[Ir(cod)Cl]₂  5 mol % 24 60° C. 22%  0% >20:1 −82% 3 [Ir(cod)Cl]₂  5 mol% 25 60° C. 26%  0% >20:1 −87% 4 [Ir(cod)Cl]₂  5 mol % 26 60° C. 30% 0% >20:1   80% 5 [Ir(cod)Cl]₂  5 mol % 27 60° C. 83% 10% >20:1   94% 6[Ir(cod)Cl]₂  5 mol % 27 80° C. 31% 43% >20:1   87% 7 [Ir(cod)Cl]₂  5mol % 27 60° C.  7%  51%^(f) >20:1    94%^(g)  80° C.^(e) 8 [Ir(cod)Cl]₂10 mol % 27 60° C.  3%  63%^(f) >20:1    94%^(g)  80° C.^(e)

Table 1 above reports the results of the development of theenantioselective hydrogenation. Unless otherwise noted, all reac-tionswere run in 9:1 toluene:acetic acid (0.02 M) in the presence oftetra-n-butylammonium iodide (an iodide-to-iridium ratio of 3:1 wasmaintained in all cases) under a pressurized (60 bar) hydro-genatmosphere for 18 hr. ^(a)Measured by absorption at 230 nm on UHPLC-MSvs. 1,2,4,5-tetrachlorobenzene internal standard unless otherwise noted.^(b)Measured by ¹H-NMR analysis of the crude reaction mixture. Measuredfor compound 23 for entries 1-4; measured for compound 6 for entries5-8. ^(c)Measured on N-acetyl 23 after treating the crude reactionmixture with Ac2O and isolating the product via thin-layerchromatography. ^(d)A ligand-to-catalyst ratio of 1.2:1 was maintainedin all cases. ^(e)Reaction performed at 60° C. for 18 hr, then thetemperature was raised to 80° C. and maintained at that temperature for24 hr. ^(f)Yield of isolated product. ^(g)Measured on compound 6 afterits isolation. Dr is diastereomeric ratio (e.g., desired isomer vs. allother isomers); ee is enantiomeric excess; cod is 1,5-cyclooctadiene;TBAI is tetra-n-butylammonium iodide; ND is not determined; BTFM 15bis-trifluoromethyl.

Upon beginning our enantioselective hydrogenation studies, we found thatwe could achieve trace amounts of mono-THIQ 23 by utilizing a catalystmixture composed of [Ir(cod)Cl]2 (cod=1,5-cyclooctadiene), Xyliphos, andtetra-n-butylammonium iodide in a solvent mixture of 9:1 toluene:aceticacid (Table 1, Entry 1, 2% yield),⁴¹ thus confirming the acceleratingeffects of hydroxyl direction. Utilizing these general conditions, weperformed a very broad evaluation of more than 60 chiral ligandscommonly used in enantioselective catalysis protocols.

From this survey, we initially identified three ligands that provided 23in at least 80% enantiomeric excess (ee) and with uniformly excellentdiastereoselectivity (all>20:1 dr): S—(CF₃)-t-BuPHOX (24, Entry 2, 22%yield, 82% ee), S,S-Et-FerroTANE (25, Entry 3, 26% yield, −87% ee), andS,R_(P)-Xyliphos (26, Entry 4, 30% yield, 80% ee). After evaluating eachof these ligand classes further, we identified S,R_(P)-BTFM-Xyliphos(42) as a strongly activating ligand that provided mono-THIQ 23 in 83%yield, >20:1 dr, and in a remarkable 94% ee (Entry 5), thus confirmingthe stereochemical rationale presented above. Moreover, we were pleasedto find that ligand 26 formed a catalyst that provided pentacycle 6 in10% yield. Further evaluation of the reaction parameters revealed thatincreasing temperature provided higher levels of reactivity, albeit atthe expense of enantioselectivity (Entry 6, 31% yield of 23, 43% yieldof 6, >20:1 dr, 87% ee). Ultimately, the best results were achieved byperforming the reaction at 60° C. for 18 hours followed by increasingthe temperature to 80° C. for 24 hours.

Utilizing these conditions, 6 was isolated in 51% yield with >20:1 drand 94% ee (Entry 7). In the end, doubling the catalyst loading allowedus to isolate 6 in 63% yield, also with >20:1 dr and 94% ee (Entry 8).Within the context of this synthesis, the relatively high catalystloading (20 mol % Ir) is mitigated to a great extent by the substantialamount of complexity generated in this single trans-formation.

The final steps of our total synthesis of jorumycin are shown above.Reductive methylation and dibromination of the ar-omatic terminiproceeded smoothly in 89% and 88% yield, respectively. Lithiation ofthis species was achieved in THF at −78° C., and quenching this dianionwith trimethylborate yielded an intermediate bis-boronic ester (notshown) which was not stable to isolation; however, oxidation of thisspecies occurred upon the addition water and sodium perborate to thecrude reaction mixture, directly providing bis-phenol 29. Exposure of 29to lithium diethoxyaluminum hydride (43) cleanly reduced the lactam tothe desired carbinolamine. Due to the known instability of thisspecies,¹⁶⁻¹⁹ the reaction was quenched with hydro-gen cyanide,affording the corresponding α-cyanoamine in 63% yield. Oxidation of thearenes proceeded in 69% yield (17) to deliver bisquinone 30, a naturalproduct known as Jor-unnamycin A. Our synthesis was completed using aknown two-step sequence for acylation and hydrolysis of theα-cyanoamine, providing (−)-jorumycin (1) in 53% yield.¹⁶⁻¹⁹ In total,our synthesis requires 17 linear steps (21 total) in 0.7% overall yield.

In conclusion, we have developed a synthesis of (−)-jorumycin (1) thatis orthogonal to existing bis-THIQ syntheses in that it is not relianton highly electron-rich and it-nucleophilic aromatic rings. This willallow for the development of electron-deficient analogs that could bemore metabolically stable than the natural products themselves. Theseanalogs will have the potential to extend the still-largely untappedtherapeutic potential of the bis-THIQ family of natural products.

EXAMPLES General Information

Unless stated otherwise, reactions were performed at ambient temperature(23° C.) in flame-dried glassware under an argon atmosphere using dry,deoxygentated solvents (distilled or passed over a column of activatedalumina). Commercially available reagents were used as received.Reactions requiring external heat were modulated to the specifiedtemperatures using an IKAmag temperature controller. Thin-layerchromatography (TLC) was performed using E. Merck silica gel 60 F254pre-coated plates (250 nm) and visualized by UV fluorescence quenchingor potassium permanganate staining. Silicycle SiliaFlash P60 AcademicSilica gel (particle size 40-63 nm) was used for flash chromatography.Purified water was obtained using a Barnstead NANOpure Infinity UV/UFsystem. ¹H and ¹³C NMR spectra were recorded on a Varian Inova 500 (500MHz and 126 MHz, respectively) and a Bruker AV III HD spectrometerequipped with a Prodigy liquid nitrogen temperature cryoprobe (400 MHzand 101 MHz, respectively) and are reported in terms of chemical shiftrelative to CHCl₃ (δ 7.26 and 77.16, respectively). ¹⁹F and ³¹P NMRspectra were recorded on a Varian Inova 300 (282 MHz and 121 MHz,respectively). Data for ¹H NMR spectra are reported as follows: chemicalshift (δ ppm) (multiplicity, coupling constant, integration). Infrared(IR) spectra were recorded on a Perkin Elmer Paragon 1000 Spectrometerand are reported in frequency of absorption (cm⁻¹). Analytical chiralSFC was performed with a Mettler SFC supercritical CO₂ analyticalchromatography system with Chiralpak (AD-H) or Chiracel (OD-H) columnsobtained from Daicel Chemical Industries, Ltd. High resolution massspectra (HRMS) were obtained from the Caltech Center for Catalysis andChemical Synthesis using an Agilent 6200 series TOF with an AgilentG1978A Multimode source in mixed (Multimode ESI/APCI) ionization mode.Optical rotations were measured on a Jasco P-2000 polarimeter using a100 mm path-length cell at 589 nm.

Example 1: Synthesis of Isoquinoline-N-Oxide 9

3,5-dimethoxy-4-methylbenzaldehyde (S2)

The procedure was adapted from the method of Comins et al.^(i)N-methylpiperazine (670 μL, 6.6 mmol, 1.1 equiv) was dissolved in 20 mLTHF and cooled to −20° C. n-Butyllithium (2.4 M, 2.65 mL, 6.3 mmol, 1.05equiv) was added in a dropwise fashion, resulting in an orange solution.The solution was stirred at this temperature 15 min before a solution of3,5-dimethoxybenzaldehyde (51, 1.00 g, 6.0 mmol, 1 equiv) in 3 mL THFwas added in a dropwise fashion, causing a color change to yellow. Thesolution was stirred at this temperature 30 min before a second portionof n-butyllithium (2.4 M, 7.5 mL, 18.1 mmol, 3 equiv) was added in adropwise fashion. At this the flask was stored in a −20° C. freezer for24 h. The flask was re-submerged in a −20° C. bath, and freshlydistilled methyl iodide (2.25 mL, 36.1 mmol, 6 equiv) was added in adropwise fashion, resulting in a mild exotherm. The solution was stirred30 min at −20° C. and was removed from its bath, warming to roomtemperature. After 30 min the reaction was quenched by the addition of20 mL 0.5 M HCl, and the solution was stirred 30 min without a cap. Thelayers were separated and the aqueous phase was saturated with sodiumchloride. The aqueous phase was extracted with Et₂O, dried over MgSO₄and concentrated. The product was purified by column chromatography (10%EtOAc/hex). Colorless solid, 1.03 g, 5.72 mmol, 95% yield. NMR spectrawere identical to the previously reported compound.² ¹H NMR (400 MHz,CDCl₃) δ 9.88 (s, 1H), 7.03 (s, 2H), 3.87 (s, 6H), 2.14 (s, 3H); ¹³C NMR(101 MHz, CDCl₃) δ 192.0, 158.7, 135.1, 122.5, 104.7, 55.9, 9.0.

2-Bromo-3,5-dimethoxy-4-methylbenzaldehyde (11)

Aldehyde S1 (8.62 g, 47.8 mmol, 1 equiv) was dissolved in CH₂Cl₂ (100mL, 0.5 M) and acetic acid (30 μL, 0.5 mmol, 0.01 equiv) was added. Thesolution was cooled to 0° C. before bromine was added in a slow,dropwise fashion. The solution was stirred 30 min after completeaddition at 0° C., at which time TLC (10% EtOAc/hex) showed completeconversion. The reaction was quenched by the addition of 10% aqueoussodium thiosulfate and saturated NaHCO₃solution. The layers wereseparated and the aqueous phase was extracted with CHCl₃. The combinedorganic phases were washed with water, dried over MgSO₄ andconcentrated. The product was purified by dissolving in −50 mL boilinghexanes, under which conditions the trace amounts of dibromide areinsoluble. The solution was filtered while boiling, providing the pureproduct. Colorless solid, 10.13 g, 39.1 mmol, 82% yield. NMR spectrawere identical to the previously reported compound.^(ii 1)H NMR (400MHz, CDCl₃) δ 10.33 (s, 1H), 7.21 (s, 1H), 3.87 (s, 3H), 3.81 (s, 3H),2.25 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 191.8, 158.2, 156.2, 132.2,129.5, 114.9, 106.0, 60.8, 56.1, 10.6.

(E)-2-(3-((tert-butyldimethylsilyl)oxy)prop-1-yn-1-yl)-3,5-dimethoxy-4-methylbenzaldehydeoxime (13)

Bromide 11 (19.4 g, 74.9 mmol, 1 equiv), (PPh₃)₂PdCl₂ (2.6 g, 3.70 mmol,0.05 equiv), and CuI (714 mg, 3.75 mmol, 0.05 equiv) were slurried indiisopropylamine (300 mL, 0.25 M, freshly distilled from CaH₂) in a 2liter 3-necked roundbottom flask, and the orange suspension was spargedwith N₂ for 10 min. O-tert-butyldimethylsilyl propargyl alcohol^(iii)(12, 17.3 g, 101 mmol, 1.35 equiv) was added in one portion, causing thesuspension to darken as the palladium catalyst was reduced. Thesuspension was sparged with N₂ for a further 1 min, then heated to 70°C. for 24 h. At this stage, TLC and LCMS indicated complete conversionof bromide 11, so the suspension was cooled to 50° C. and 200 mL MeOHwas added. Hydroxylamine hydrochloride (6.24 g, 89.8 mmol, 1.2 equiv)was added in one portion and the solution was heated to reflux (85° C.)for 2 h. At this stage, TLC and LCMS indicated complete conversion tothe product. The solution was cooled to room temperature and Celite(˜100 g) was added. The suspension was filtered through a pad of celite,topped with sand, eluting with ethyl acetate. The filtrate wasconcentrated and purified by column chromatography (15% EtOAc/hex).Colorless solid, 26.9 g, 74.1 mmol, 99% yield. ¹H NMR (500 MHz, CDCl₃) δ8.60 (s, 1H), 7.46 (s, 1H), 7.10 (s, 1H), 4.62 (s, 2H), 3.86 (s, 6H),2.15 (s, 3H), 0.95 (s, 9H), 0.18 (s, 6H); ¹H NMR (500 MHz, CDCl₃) δ160.5, 159.8, 149.5, 132.8, 122.5, 110.3, 101.9, 96.2, 78.2, 61.0, 55.9,52.6, 26.0, 18.5, 9.3, −5.0; IR (thin film, NaCl): 3270.1, 3092.6,2997.3, 1953.8, 2932.4, 2896.1, 2857.0, 2221.2, 1611.1, 1591.7, 1560.0,1463.8, 1402.9, 1383.9, 1331.8, 1281.5, 1255.3, 1217.9, 1191.5, 1164.3,1136.9, 1121.1, 1101.2, 1080.0, 1034.8, 977.1, 903.5, 837.9, 779.7,722.1, 704.2, 671.8; HRMS (ESI-TOF) calc'd for [M⁺]C₁₉H₂₉NO₄Si=363.1866, found 363.1939.

3-(((tert-butyldimethylsilyl)oxy)methyl)-5,7-dimethoxy-6-methylisoquinoline-N-oxide(9)

Oxime 13 (15.92 g, 45.7 mmol, 1 equiv) was dissolved in CH₂Cl₂ (460 mL,0.1 M) and the flask was vacuum purged and refilled with nitrogen fivetimes, then heated to reflux. AgOTf (235 mg, 0.91 mmol, 0.02 equiv) wasadded in one portion to the refluxing solution, resulting in a rapid andmildly exothermic reaction. The reaction flask was shielded from lightand maintained at reflux for 15 min, at which time LCMS indicated fullconversion to the product. The solution was filtered through a 1 inchpad of silica with 500 mL CH₂Cl₂ and 1 L 10% MeOH/EtOAc. Silica gel (40mL) was added to the second portion of filtrate, which was thenconcentrated. The product was purified by column chromatography using a6 inch pad of silica (30-50-100% EtOAc/CH₂Cl₂; then 2-5-10-20%MeOH/EtOAc+1% NEt₃). Colorless solid, 12.27 g, 33.8 mmol, 77% yield. Theproduct is initially isolated as a black solid that is spectroscopicallypure, and can be recrystallized to a colorless solid from minimalboiling heptanes. Very little mass is lost during this process (lessthan 50 mg from a 12 g batch), indicating the presence of very minor yethighly colored impurities. ¹H NMR (400 MHz, CDCl₃) δ 8.65 (s, 1H), 8.02(s, 1H), 6.71 (s, 1H), 5.01 (d, J=1.4 Hz, 2H), 3.92 (s, 3H), 3.87 (s,3H), 2.27 (s, 3H), 1.00 (s, 9H), 0.15 (s, 6H); ¹³C NMR (101 MHz, CDCl₃)δ 159.4, 153.7, 145.9, 135.2, 128.4, 123.6, 120.1, 115.0, 97.4, 61.7,60.1, 55.9, 26.0, 18.4, 9.8, −5.3; IR (thin film, NaCl): 3390.3, 3073.7,2998.1, 2953.8, 2892.2, 2857.2, 1637.3, 1613.4, 1567.8, 1470.6, 1390.6,1371.6, 1341.4, 1308.3, 1254.2, 1209.7, 1185.3, 1148.0, 1116.4, 1020.7,1007.1, 957.4, 899.7, 838.8, 808.0, 777.9, 701.7, 669.8, 637.7; HRMS(ESI-TOF) calc'd for [M⁺] C₁₉H₂₉NO₄Si=363.1866, found 363.1863.

Example 2: Synthesis of Isoquinoline Triflate 10

3,4-Dimethoxy-5-methylphenyl isopropylcarbamate (S4)

In a nitrogen-filled glovebox, [Ir(cod)OMe]2 (22.3 mg, 0.034 mmol, 0.005equiv) and 3,4,7,8-tetramethyl-1,10-phenanthroline (15.9 mg, 0.067 mmol,0.01 equiv) were dissolved in 5 mL THF and stirred 30 min. In themeantime, 2,3-dimethoxytoluene (1.00 mL, 6.73 mmol, 1 equiv) and B₂Pin₂(1.28 g, 5.05 mmol, 0.75 equiv) were weighed into a 20 mL sealablemicrowave vial (also in the glovebox) with a teflon-coated stir bar and5 mL THF was added. Upon complete dissolution, the catalyst solution wastransferred to the microwave vial, which was sealed prior to removingfrom the glovebox. The vial was then placed in a preheated 80° C. oilbath and stirred 48 h, at which time TLC (20% EtOAc/hex) revealedcomplete conversion to a single borylated product. The vial was cooledto room temperature and the cap was removed. N-methylmorpholine-N-oxide(2.37 g, 20.2 mmol, 3 equiv) was added in a few small portions and thevial was resealed and returned to the 80° C. oil bath for 3 h, at whichtime TLC (20% EtOAc/hex) indicated complete oxidation to theintermediate phenol. Triethylamine (4.7 mL, 33.7 mmol, 5 equiv) andisopropyl isocyanate (2.6 mL, 26.9 mmol, 4 equiv) were added at 23° C.and the solution was stirred 16 h, at which time TLC (50% EtOAc/hex)indicated complete conversion to carbamate S4. The contents of the vialwere transferred to a 100 mL roundbottom flask and 10% aq. Na₂S₂O₃ wasadded to quench the remaining oxidant and citric acid hydrate (4.5 g, >3equiv) was added to chelate the boron. This solution was stirred 1 h,and concentrated HCl was added 1 mL at a time until an acidic pH wasachieved. The layers were separated and the aqueous phase was extractedwith EtOAc. The combined organic phases were then washed with aqueousK₂CO₃, dried over MgSO₄ and concentrated. The product was purified bycolumn chromatography (25% EtOAc/hex). Colorless solid, 1.16 g, 4.6mmol, 68% yield. NMR spectra were identical to the previously reportedcompound.^(iv 1)H NMR (400 MHz, CDCl₃) δ 6.55 (d, J=2.6 Hz, 1H), 6.52(d, J=2.8 Hz, 1H), 4.84 (d, J=7.8 Hz, 1H), 3.88 (ddd, J=16.1, 13.9, 7.6Hz, 1H), 3.82 (s, 3H) 3.76 (s, 3H), 2.24 (s, 3H), 1.23 (s, 3H), 1.21 (s,3H); ¹³CH NMR (101 MHz, CDCl₃) δ 154.0, 153.0, 146.8, 144.7, 132.3,115.4, 104.3, 60.3, 55.9, 43.6, 23.0, 16.0.

3,4-Dimethoxy-5-methyl-2-(trimethylsilyl)phenyl isopropylcarbamate (S5)

Vigorous stirring was required throughout the course of the reaction dueto the formation of insoluble triflate salts. Carbamate S4 (17.30 g,68.2 mmol, 1 equiv) was dissolved in Et₂O (340 mL, 0.2 M)N,N,N′,N′-tetramethylethylenediamine (TMEDA, 11.3 mL, 75.1 mmol, 1.1equiv) was added and the solution was cooled to 0° C. beforetert-butyldimethylsilyl triflate (TBSOTf, 17.25 mL, 75.1 mmol, 1.1equiv) was added in a slow stream. The solution was stirred 10 min at 0°C., removed from the ice bath and stirred at 23° C. for 30 min. A secondportion of TMEDA (41 mL, 273 mmol, 4 equiv) was added and the solutionwas cooled to −78° C. n-Butyllithium (2.4 M, 114 mL, 274 mmol, 4 equiv)was added in a dropwise fashion through a flame-dried addition funnelover the course of 1 h, being sure to not let the temperature risesignificantly. The resulting yellow suspension was stirred vigorouslyfor 4 h at −78° C., taking care not to let the temperature rise.Trimethylsilyl chloride (61 mL, 478 mmol, 7 equiv) was then addeddropwise via the addition funnel over the course of 30 min and thesuspension was stirred at −78° C. for 30 min, then was removed from thedry ice bath and stirred at 23° C. for 16 h. The reaction was quenchedby the addition of 300 mL aqueous NH₄Cl (30 mL saturated solutiondiluted to 300 mL) through an addition funnel, the first 50 mL of whichwere added dropwise, followed by the addition of the remainder in a slowstream. The aqueous phase was then further acidified by the addition ofsmall portions of concentrated HCl until an acidic pH was achieved (˜30mL required). The layers were separated and the aqueous phase wasextracted twice with Et₂O. The combined organic phases were washed withsaturated aqueous NH₄Cl, dried over MgSO₄ and concentrated. The productwas purified by column chromatography (20-30% Et₂O/hex). Colorlesssolid, 20.61 g, 63.3 mmol, 93% yield. NMR spectra were identical to thepreviously reported compound.⁵ ¹H NMR (300 MHz, CDCl₃) δ 6.63 (s, 1H),4.69 (d, J=8.1 Hz, 1H), 3.96-3.85 (m, 1H), 3.83 (s, 3H), 3.76 (s, 3H),2.23 (s, 3H), 1.23 (s, 3H), 1.21 (s, 3H), 0.28 (s, 9H); 157.9, ¹³C NMR(126 MHz, CDCl₃) δ 157.9, 154.2, 150.5, 148.5, 134.6, 123.0, 120.1,60.5, 59.8, 43.5, 23.1, 16.1, 1.3.

3,4-Dimethoxy-5-methyl-2-(trimethylsilyl)phenyltrifluoromethanesulfonate (14)

Carbamate S5 (8.08 g, 24.8 mmol, 1 equiv) was dissolved in THF (100 mL,0.25 M) and diethylamine (3.85 mL, 37.2 mmol, 1.5 equiv) was added andthe solution was cooled to −78° C. n-Butyllithium (2.5 M, 15 mL, 37.5mmol, 1.5 equiv) was added slowly over the course of 15 min. Thesolution was stirred at that temperature for 30 min, then removed fromits bath and stirred at 23° C. for 30 min. N-Phenyl triflimide (10.6 g,29.8 mmol, 1.2 equiv) was added in one portion and the solution wasstirred 30 min. A second portion of diethylamine (4.6 mL, 44.7 mmol, 1.8equiv) was added and the solution was stirred 2 h. The solution wasfiltered through a 1 inch pad of silica gel with 50% Et₂O/hex andconcentrated. The product was purified by column chromatography (10%Et₂O/hex). Arene 14 can be isolated as a colorless oil, but undergoesdecomposition and should be used within the day of its isolation.Colorless oil, 9.15 g, 24.6 mmol, 99% yield. NMR spectra were identicalto the previously reported compound.⁵ ¹H NMR (400 MHz, CDCl₃) δ 6.87 (s,1H), 3.86 (s, 3H), 3.77 (s, 3H), 2.27 (d, J=0.7 Hz, 3H), 0.36 (s, 9H);¹³C NMR (101 MHz, CDCl₃) δ 158.5, 150.4, 149.0, 135.6, 124.2, 118.7 (q,J=320.6 Hz), 117.7, 60.6, 59.8, 16.3, 1.2; ¹⁹F NMR (282 MHz, CDCl₃) δ−73.1 (s, 3F).

7,8-Dimethoxy-1,6-dimethyl-3-hydroxyisoquinoline (16)

Cesium fluoride (204 mg, 1.34 mmol, 2.5 equiv) was dissolved inacetonitrile (5.4 mL, 0.1 M) in a 20 mL microwave vial and water (9.7μL, 0.537 mmol, 1.0 equiv) and methyl acetoacetate (58 μL, 0.537 mmol,1.0 equiv) were added. Aryne precursor 14 (250 mg, 0.671 mmol, 1.25equiv) was added neat via syringe, and the vial was placed in apreheated 80° C. oil bath. After 2 h, TLC revealed complete consumptionof 14, so NH₄OH (28-30%, 5.4 mL) was added in one portion. The vial wasmoved to a preheated 60° C. oil bath and stirred 8 h. The solution waspoured into brine inside a separatory funnel and the solution wasextracted with EtOAc (2×30 mL). The aqueous phase was brought to pH 7 bythe addition of concentrated HCl and was extracted with EtOAc (2×30 mL).The aqueous phase was discarded. The organic phase was then extractedwith 2M HCl (5×20 mL). The organic phase was checked by LCMS to confirmthat all of product 16 had transferred to the aqueous phase and wassubsequently discarded. The aqueous phase was then brought back to pH 7by the addition of 100 mL 2M NaOH and was extracted with EtOAc (5×20mL). The combined organic phases were washed with brine, dried overNa₂SO₄ and concentrated, providing the product. Yellow solid, 56.9 mg,0.243 mmol, 45% yield. NMR (300 MHz, CDCl₃) δ 6.95 (d, J=0.7 Hz, 1H),6.53 (s, 1H), 3.93 (s, 3H), 3.84 (s, 3H), 3.05 (d, J=0.7 Hz, 3H), 2.31(d, J=1.0 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 161.7, 149.4, 145.8,142.5, 140.3, 121.3, 113.0, 104.7, 60.4, 60.1, 21.0, 17.2; IR (thinfilm, NaCl): 3327.0, 2937.6, 2608.7, 1651.7, 1455.4, 1324.2, 1226.8,1177.9, 1147.2, 1089.5, 1062.3, 1034.8, 1000.5, 960.0, 937.7, 892.4,861.7, 813.2, 724.1, 682.8, 662.3; FIRMS (ESI-TOF) calc'd for [M⁺]C₁₃H₁₅NO₃=233.1052, found 233.1057.

7,8-Dimethoxy-1,6-dimethyl-3-(trifluoromethanesulfonyloxy)isoquinoline(10)

Hydroxyisoquinoline 16 (2.60 g, 11.1 mmol, 1 equiv) was dissolved inCH₂Cl₂ (70 mL, 0.16 M) and pyridine (11.4 mL, 140.6 mmol, 12.7 equiv)was added and the solution was cooled to 0° C. Trifluoromethanesulfonicanhydride (Tf₂O, 3.00 mL, 17.8 mmol, 1.6 equiv) was added dropwise,causing the yellow solution to turn dark red. After 30 min TLC (10%EtOAc/hex) revealed complete conversion, so the reaction was quenched bythe addition of saturated aqueous NaHCO₃ (70 mL). The solution wasstirred vigorously until bubbling ceased, at which time the layers wereseparated. The organic phase was extracted with CH₂Cl₂ and the combinedorganic phases were dried over Na₂SO₄ and concentrated. The product waspurified by column chromatography (10% Et₂O/hex). Yellow oil, 3.82 g,10.5 mmol, 94% yield. ¹H NMR (400 MHz, CDCl₃) δ 7.39 (d, J=1.0 Hz, 1H),7.21 (s, 1H), 3.98 (s, 3H), 3.93 (s, 3H), 3.07 (d, J=0.7 Hz, 3H), 2.44(d, J=1.0 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 158.6, 151.0, 150.5,149.9, 139.2, 136.8, 123.6, 122.9, 118.8 (q, J=320.5 Hz), 107.6, 60.8,60.2, 26.7, 17.0; ¹⁹F NMR (282 MHz, CDCl₃) δ −72.99; IR (thin film,NaCl): 3436.0, 2939.4, 1605.5, 1553.6, 1493.7, 1415.9, 1381.0, 1351.9,1332.9, 1248.8, 1209.3, 1133.6, 1097.0, 1059.9, 1009.8, 983.4, 966.2,940.7, 892.0, 834.7, 768.1, 695.0, 649.3, 608.2; HRMS (ESI-TOF) calc'dfor [M⁺] C₁₄H₁₄F₃NO₅S=365.0545, found 365.0547.

Example 3: Fagnou Cross-Coupling Reaction

3-(((tert-butyldimethylsilyl)oxy)methyl)-5,7,7′,8′-tetramethoxy-1′,6,6′-trimethyl-[1,3′-biisoquinoline]2-oxide (18)

Palladium acetate (347 mg, 1.54 mmol, 0.20 equiv),di-tert-butyl(methyl)phosphonium tetrafluoroborate (957 mg, 3.86 mmol,0.50 equiv), and cesium carbonate (1.26 g, 3.41 mmol, 0.50 equiv) wereweighed into a 100 mL pear-shaped flask and brought into anitrogen-filled glovebox and cesium pivalate (CsOPiv, 722 mg, 3.09 mmol,0.40 equiv) was added to the flask. In the glovebox, degassed toluene(80 mL) was added, the flask was sealed with a rubber septum and removedfrom the glovebox, to be placed in a 60° C. preheated oil bath, where itwas stirred for 30 min and allowed to cool to room temperature. In themeantime, N-oxide 9 (8.42 g, 23.1 mmol, 3 equiv) and cesium carbonate(7.54 g, 23.1 mmol, 3 equiv) were weighed into a 250 mL sealable flaskequipped with a Kontes valve, to which 50 mL toluene was added, and thissuspension was sparge-degassed with nitrogen for 10 min. Isoquinolinetriflate 10 (2.77 g, 6.82 mmol, 1.00 equiv) was dissolved in 10 mLtoluene, which was sparge-degassed with nitrogen for 10 min. Thesolution of isoquinoline triflate 10 was then added via cannula to thecooled catalyst solution, rinsing the flask with 5 mL degassed toluene.The catalyst/triflate solution was then added via cannula to the 250 mLsealable flask, rinsing with 10 mL degassed toluene. The flask wassealed and placed in a 130° C. preheated oil bath for 4.5 h. The flaskwas then allowed to cool to room temperature and Celite (10 g) wasadded. This suspension was then filtered through a 1 inch pad of Celitethat was topped with sand, rinsing with CH₂Cl₂ and acetone (500 mLeach). The solution was concentrated, providing the crude product. ¹HNMR of the crude reaction mixture showed a 2:1 mixture ofbis-isoquinoline 18 and N-oxide 9 at this point, indicating completeconversion to product. The product was purified by column chromatography(10-20% EtOAc/hex, then 20-50-100% EtOAc/hex+1% NEt₃, then 10-20%MeOH/EtOAc+1% NEt₃. bis-Isoquinoline 18 elutes during the 50-100%EtOAc/hex portion, and remaining N-oxide 9 elutes during the 10-20%MeOH/EtOAc portion). Colorless foam, 3.88 g, 6.70 mmol, 98% yield. Ananalogous coupling performed with 2.39 g isoquinoline triflate 10provided 3.30 g of product (87% yield), together providing 7.18 gbis-isoquinoline 18 in 93% average yield. ¹H NMR (400 MHz, CDCl₃) δ 8.13(d, J=0.9 Hz, 1H), 7.81 (s, 1H), 7.42 (d, J=1.1 Hz, 1H), 6.60 (s, 1H),5.06 (d, J=1.4 Hz, 2H), 4.01 (s, 3H), 3.97 (s, 3H), 3.90 (s, 3H), 3.65(s, 3H), 3.17 (s, 3H), 2.45 (d, J=0.9 Hz, 3H), 2.28 (s, 3H), 1.03 (s,9H), 0.17 (s, 6H); ¹³C NMR (101 MHz, CDCl₃) δ 158.9, 157.8, 153.8,151.3, 149.6, 146.0, 143.7, 142.0, 137.6, 134.8, 128.2, 124.3, 122.7,122.5, 121.5, 120.4, 114.5, 98.6, 61.8, 60.9, 60.4, 60.3, 27.2, 25.7,18.5, 17.1, 9.7, −5.2; IR (thin film, NaCl): 3417.9, 2954.4, 2856.9,1614.6, 1567.0, 1463.4, 1392.7, 1328.6, 1255.0, 1213.2, 1189.5, 1139.2,1117.7, 1089.2, 1057.0, 1008.0, 961.2, 936.5, 897.0, 839.1, 815.5,778.4, 734.4, 701.8, 634.2; FIRMS (ESI-TOF) calc'd for [M⁺]C₃₂H₄₂N₂O₆Si=578.2812, found 578.2796.

Example 4: First-Generation Synthesis of bis-Isoquinoline 22

3-(((Tert-butyldimethylsilyl)oxy)methyl)-5,7,7′,8′-tetramethoxy-1′,6,6′-trimethyl-1,3′-biisoquinoline(S8)

Bis-isoquinoline-N-oxide 18 (6.16 g, 10.6 mmol, 1.00 equiv) wasdissolved in CH₂Cl₂ (210 mL, 0.05 M) and the solution was cooled to 0°C. Neat phosphorus trichloride (1.86 mL, 21.3 mmol, 2.00 equiv) wasadded at a dropwise pace over 5 minutes, causing the solution toimmediately turn dark purple. After 30 min, TLC revealed completeconversion to the product, so the reaction was quenched with saturatedaqueous K₂CO₃ and diluted with water. The layers were separated and theaqueous phase was extracted with EtOAc. The combined organic phases weredried over Na₂SO₄ and concentrated (note: a brine wash caused asignificant emulsion regardless of extraction solvent, and was avoided).The product was purified by column chromatography (10% EtOAc/hex+1%NEt₃). Yellow solid, 5.44 g, 9.67 mmol, 91% yield). ¹H NMR (400 MHz,CDCl₃) δ 8.03 (q, J=1.1 Hz, 1H), 8.01 (s, 1H), 7.89 (s, 1H), 7.48 (d,J=0.6 Hz, 1H), 5.08 (d, J=1.2 Hz, 2H), 4.02 (s, 3H), 3.97 (s, 3H), 3.91(s, 3H), 3.85 (s, 3H), 3.21 (s, 3H), 2.46 (d, J=0.9 Hz, 3H), 2.35 (s,3H), 1.03 (s, 9H), 0.17 (s, 6H); ¹³C NMR (101 MHz, CDCl₃) δ 157.3,155.9, 155.3, 153.5, 152.1, 150.8, 150.4, 149.5, 137.2, 135.4, 128.9,125.7, 124.4, 124.0, 122.0, 119.6, 110.3, 101.0, 66.3, 61.5, 60.8, 60.2,55.5, 27.1, 26.0, 18.5, 17.0, 9.7, −5.2.

(5,7,7′,8′-Tetramethoxy-1′,6,6′-trimethyl-[1,3′-biisoquinolin]-3-yl)methanol(S6)

Bis-isoquinoline S8 (5.44 g, 9.7 mmol, 1.00 equiv) was dissolved inacetic acid (40 mL, 0.25 M) and solid potassium fluoride (2.81 g, 48.0mmol, 5.00 equiv) was added in one portion. The solution was stirred 30min at room temperature, at which time LCMS showed complete conversionto the product. The solution was diluted with CH₂Cl₂ and ice and thesolution was stirred vigorously as a solution of sodium hydroxide (25 g,0.625 mol, 0.9 equiv relative to 40 mL AcOH) in 70 mL water was addedslowly. The rest of the acetic acid was quenched by the addition ofsaturated aqueous K₂CO₃. The layers were separated and the aqueous phasewas extracted with CH₂Cl₂. The combined organic phases were washed withbrine, dried over Na₂SO₄ and concentrated. The product was purified bycolumn chromatography (1-2-3-4-5% MeOH/CH₂Cl₂+1% NEt₃). Colorless solid,4.17 g, 9.31 mmol, 96% yield. ¹H NMR (400 MHz, CDCl₃) δ 8.09 (s, 1H),8.03 (s, 1H), 7.79 (d, J=0.9 Hz, 1H), 7.49 (d, J=1.1 Hz, 1H), 4.94 (s,2H), 4.03 (s, 3H), 3.97 (s, 3H), 3.89 (s, 3H), 3.87 (s, 3H), 3.22 (s,3H), 2.47 (d, J=1.0 Hz, 3H), 2.35 (s, 4H); ¹³C NMR (101 MHz, CDCl₃) δ157.8, 156.0, 155.2, 153.5, 151.1, 150.3, 149.7, 149.6, 137.6, 135.4,129.0, 126.2, 124.7, 124.6, 122.2, 119.9, 111.3, 101.3, 65.0, 61.7,60.9, 60.3, 55.6, 27.2, 17.1, 9.9; IR (thin film, NaCl): 3352.3, 3128.9,2936.6, 2855.0, 1620.4, 1594.1, 1556.8, 1484.4, 1462.2, 1454.9, 1416.4,1392.3, 1355.0, 1331.4, 1303.1, 1243.0, 1218.0, 1195.9, 1133.0, 1117.1,1090.7, 1059.8, 1008.2, 963.5, 906.0, 884.5, 841.2, 795.7, 732.6, 645.8;HRMS (ESI-TOF) calc'd for [M+] C₂₆H₂₈N₂O₅=448.1998, found 448.1992.

Methyl5,7,7′,8′-tetramethoxy-1′,6,6′-trimethyl-[1,3′-biisoquinoline]-3-carboxylate(S7)

bis-Isoquinoline S6 (1.50 g, 3.34 mmol, 1.00 equiv) and silver(I) oxide(3.88 g, 16.7 mmol, 5.00 equiv) were slurried in MeOH (35 mL, 0.1 M).After 30 min, the solution appeared to be fully homogeneous and deep redin color. After 4 h, LCMS showed full conversion to a mixture of methylester S7 and the corresponding carboxylic acid. Thionyl chloride (1.21mL, 16.7 mmol, 5.00 equiv) was added through the top of a refluxcondenser, and following the complete addition the solution was heatedto reflux After 1.5 LCMS showed complete conversion to methyl ester S7.The solution was cooled to room temperature and celite was added, andthe solution was filtered through more celite, rinsing with EtOAc. Thesolution was concentrated, then redissolved in CH₂Cl₂ and was washedwith dilute aqueous K₂CO₃ and brine. The layers were separated and theaqueous phase was extracted with CH₂Cl₂. The combined organic phaseswere washed with brine, dried over Na₂SO₄ and concentrated. The productwas purified by column chromatography (25% EtOAc/hex+1% NEt₃). Whitesolid, 1.40 g, 2.94 mmol, 88% yield. ¹H NMR (400 MHz, CDCl₃) δ 8.75 (d,J=0.9 Hz, 1H), 8.19 (s, 1H), 8.13 (s, 1H), 7.52 (d, J=1.1 Hz, 1H), 4.05(s, 3H), 4.01 (s, 3H), 3.97 (s, 3H), 3.94 (s, 3H), 3.90 (s, 3H), 3.20(s, 3H), 2.46 (d, J=1.0 Hz, 3H), 2.36 (s, 3H); ¹H NMR (400 MHz, CDCl₃) δ167.0, 160.0, 156.0, 155.8, 154.9, 151.1, 149.9, 149.5, 139.0, 137.5,135.6, 128.6, 128.0, 125.0, 124.7, 122.3, 120.5, 118.6, 101.9, 62.3,60.9, 60.3, 55.8, 52.8, 27.1, 17.1, 9.9; IR (thin film, NaCl): 3443.0,2948.7, 1714.1, 1614.7, 1454.4, 1407.2, 1384.3, 1330.3, 1304.7, 1270.1,1226.4, 1136.9, 1088.6, 1057.2, 1008.0, 870.5, 786.0, 733.2; HRMS(ESI-TOF) calc'd for [M⁺] C₂₇H₂₈N₂O₆=476.1947, found 476.1952.

MethylV-formyl-5,7,7′,8′-tetramethoxy-6,6′-dimethyl-[1,3′-biisoquinoline]-3-carboxylate(S8) and methylV-(hydroxy(methoxy)methyl)-5,7,7′,8′-tetramethoxy-6,6′-dimethyl-[1,3′-biisoquinoline]-3-carboxylate(S9)

bis-Isoquinoline S6 (1.40 g, 2.94 mmol, 1.00 equiv) and selenium dioxide(652 mg, 5.88 mmol, 2.00 equiv) was slurried in dioxane and the flaskwas fitted with a reflux condenser. The flask was vacuum purged/refilledwith N₂ five times, then heated to reflux. At about 80° C. the solutionbecame fully homogeneous. After 1 h at reflux, the flask was cooled toroom temperature and LCMS showed full conversion to aldehyde S7. Celitewas added to the crude reaction and the resulting slurry was filteredthrough more celite, rinsing with EtOAc. SiO₂ was added to the filtrateand the solution was concentrated. Due to the insolubility of theproducts, a mixture of MeOH and CH₂Cl₂ was required during purificationby column chromatography (10% MeOH/DCM+1% NEt₃). During this process,the highly electrophilic aldehyde moiety is converted to the hemiacetalin a thermodynamic 85:15 mixture favoring the hemiacetal. The twoproducts can neither be interconverted nor separated, and as such wascharacterized as a mixture. White solid, total mass=1.47 g, 85:15 molarratio of S7:S9 by ¹H NMR, corresponding to 1.25 g hemiacetal S9 (2.39mmol, 82% yield) and 220 mg S7 (0.45 mmol, 15% yield), 2.84 mmol total,97% combined yield. Aldehyde S7: ¹H NMR (400 MHz, CDCl₃) δ 10.92 (s,1H), 8.78 (s, 1H), 8.72 (s, 1H), 8.56 (s, 1H), 7.68 (d, J=1.2 Hz, 1H),4.07 (s, 3H), 4.04 (s, 3H), 4.02 (s, 3H), 3.95 (s, 3H), 3.70 (s, 3H),2.51 (d, J=1.0 Hz, 3H), 2.37 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 193.4,160.6, 154.8, 154.1, 151.8, 151.3, 151.0, 147.1, 139.2, 135.8, 128.7,128.1, 125.3, 125.0, 124.1, 121.6, 119.1, 102.0, 67.2, 60.7, 60.6, 56.3,46.1, 17.4. Hemiacetal S9: ¹H NMR (400 MHz, CDCl₃) δ 8.78 (d, J=0.8 Hz,1H), 8.44 (s, 1H), 7.97 (s, 1H), 7.61 (d, J=1.1 Hz, 1H), 6.52 (d, J=10.6Hz, 1H), 6.41 (d, J=10.6 Hz, 1H), 4.10 (s, 3H), 4.06 (s, 3H), 3.98 (s,3H), 3.98 (s, 3H), 3.92 (s, 3H), 3.63 (s, 3H), 2.48 (d, J=1.0 Hz, 3H),2.37 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 166.8, 160.3, 155.2, 154.9,152.9, 151.5, 148.6, 148.2, 138.9, 138.6, 136.5, 128.5, 127.9, 125.2,124.9, 123.4, 120.1, 118.9, 101.5, 95.2, 62.3, 60.8, 60.3, 56.0, 55.2,52.8, 17.3, 10.0. IR (thin film, NaCl): 3436.7, 2948.9, 2846.9, 1737.7,1711.2, 1619.9, 1462.1, 1386.6, 1304.0, 1272.2, 1228.6, 1136.2, 1086.2,1001.8, 900.5, 734.1; FIRMS (ESI-TOF) for aldehyde S7 calc'd for [M⁺]C₂₇H₂₆N₂O₇=490.1740, found 490.1742; FIRMS (ESI-TOF) for hemiacetal S9calc' d for [M⁺] C₂₈H₃₀N₂O₈=522.2002, found 522.2005.

Methyl1′-(hydroxymethyl)-5,7,7′,8′-tetramethoxy-6,6′-dimethyl-[1,3′-biisoquinoline]-3-carboxylatedichloromethane solvate (22.CH₂Cl₂)

A mixture of bis-isoquinolines S7 and S9 (2.84 mmol in total, 1.00equiv) was dissolved in CH₂Cl₂ (24 mL) and MeOH (6 mL, 0.1 M) and sodiumborohydride (36.0 mg, 0.946 mmol, 0.33 equiv) was added. The solutionimmediately bubbled in a controlled fashion for ˜1 minute, then stopped.5 minutes after the addition of sodium borohydride LCMS showed completeand selective reduction to desired product 22. The reaction was quenchedby the addition of citric acid monohydrate (594 mg, 2.84 mmol, 1.00equiv) and water and the solution was stirred at 1500 rpm for 10 min,then is basified by the addition of saturated aqueous NaHCO₃. The layerswere separated and the aqueous phase was extracted with CH₂Cl₂. Thecombined organic phases were dried over Na₂SO₄ and concentrated. Theproduct was purified by column chromatography using a 1:1 mixture ofCH₂Cl₂:EtOAc as the polar solvent (20-30-40-50-60-100% polarsolvent/hex+1% NEt₃). Colorless solid, 1.55 g, 2.68 mmol, 98% yield. Astoichiometric amount of dichloromethane could not be removed from theproduct despite extensive time on high vacuum (10 mTorr), leading to theconclusion that the product is isolated as a stoichiometricdichloromethane solvate. Aldehyde S7 and hemiacetal S9 appear to be inthermal equilibrium at 23° C. in a 4:1 v/v mixture of CH₂Cl₂:MeOH in a1:3 ratio of S7:S9. When excess NaBH₄ is utilized, competitive reductionof the methyl ester was observed; however, when NaBH₄ was employed insub stoichiometric fashion, selective reduction of S7 was observed. ¹HNMR (400 MHz, CDCl₃) δ 8.79 (d, J=0.8 Hz, 1H), 8.30 (s, 1H), 7.90 (s,1H), 7.59 (d, J=0.5 Hz, 1H), 5.55 (t, J=3.5 Hz, 1H), 5.39 (d, J=3.5 Hz,2H), 5.30 (s, 2H), 4.06 (s, 3H), 4.06 (s, 3H), 3.99 (s, 3H), 3.96 (s,3H), 3.90 (s, 3H), 2.49 (d, J=0.9 Hz, 3H), 2.38 (s, 3H); ¹H NMR (400MHz, CDCl₃) δ 166.9, 160.2, 155.8, 155.6, 155.0, 151.1, 149.1, 148.5,139.0, 138.4, 135.5, 128.5, 127.9, 125.3, 124.8, 121.6, 120.3, 118.8,101.3, 64.7, 62.4, 60.9, 60.3, 56.1, 53.4, 52.9, 17.2, 10.0; IR (thinfilm, NaCl): 3364.8, 3130.4, 2930.2, 2856.2, 1690.6, 1620.8, 1594.3,1556.6, 1462.3, 1413.2, 1391.8, 1356.6, 1330.7, 1302.1, 1258.7, 1196.3,1130.7, 1088.7, 1058.5, 1010.1, 964.2, 885.9, 838.1, 801.9, 777.4,734.0; FIRMS (ESI-TOF) calc'd for [M⁺] C₂₇H₂₈N₂O₇=492.1897, found492.1894.

Example 5: Synthesis of Intermediate S8

3-(((tert-butyldimethylsilyl)oxy)methyl)-5,7,7′,8′-tetramethoxy-1′,6,6′-trimethyl-[1,3′-biisoquinoline]2,2′-dioxide (19)

Bis-isoquinoline-N-oxide 18 (100 mg, 0.173 mmol, 1 equiv) and methyltrioxorhenium (0.8 mg, 0.0032 mmol, 0.02 equiv) were dissolved in CH₂Cl₂(1.7 mL, 0.1 M) and 35% aqueous hydrogen peroxide (26.5 μL, 0.86 mmol, 5equiv) was added. Addition of the catalyst in a single portion resultedin rapid over-oxidation, but addition in 3 portions, at least 20 minutesapart resulted in clean conversion. The solution was stirred at 1300 rpmfor 30 min, at which point a second portion of MeReO₃ (0.8 mg, 0.0032mmol, 0.02 equiv) was added. After 30 min, a third and final portion ofMeReO₃ (0.8 mg, 0.0032 mmol, 0.02 equiv) was added. After a further 30min, LCMS showed complete conversion to the bis-N-oxide, so the reactionwas quenched with aqueous sodium thiosulfate. The layers were separatedand the aqueous phase was extracted with CH₂Cl₂ until no red colorremained. bis-N-oxide 19 was not stable to Na₂SO₄, MgSO₄, or SiO₂, andas such it was neither dried nor purified by column chromatography. Thesolution was concentrated, providing the analytically pure bis-N-oxide.Red solid, 100.7 mg, 0.169 mmol, 98% yield. ¹H NMR (400 MHz, CDCl₃) δ8.18 (q, J=1.3 Hz, 1H), 7.57 (s, 1H), 7.31 (d, J=1.0 Hz, 1H), 6.41 (s,1H), 5.13 (dd, J=17.0, 1.5 Hz, 1H), 5.02 (dd, J=17.0, 1.4 Hz, 1H), 3.99(s, 3H), 3.95 (s, 3H), 3.91 (s, 3H), 3.68 (s, 3H), 3.21 (s, 3H), 2.41(d, J=1.0 Hz, 3H), 2.27 (s, 3H), 1.03 (s, 9H), 0.17 (s, 3H), 0.17 (s,3H); ¹H NMR (101 MHz, CDCl₃) δ 159.4, 153.4, 153.0, 147.6, 146.1, 145.4,138.9, 137.8, 135.5, 128.3, 126.3, 124.5, 124.5, 123.7, 122.8, 120.0,115.2, 96.8, 61.8, 61.1, 60.6, 60.2, 55.7, 26.0, 18.4, 16.9, 15.4, 9.7,−5.2, −5.2; IR (thin film, NaCl): 2933.0, 2857.5, 2218.5, 1614.0,1547.6, 1469.0, 1324.3, 1237.2, 1216.5, 1139.8, 1118.3, 1083.2, 1049.6,1007.5, 975.3, 911.7, 838.9, 778.8, 730.6, 666.0, 642.6; FIRMS (ESI-TOF)calc'd for [M⁺] C₃₂H₄₂N₂O₇Si=594.2761, found 594.2757.

3-(hydroxymethyl)-5,7,7′,8′-tetramethoxy-1′,6,6′-trimethyl-[1,3′-biisoquinoline]2,2′-dioxide (19)

Bis-isoquinoline-N-oxide 18 (500 mg, 0.86 mmol, 1 equiv) and methyltrioxorhenium (MTO, 4.3 mg, 0.017 mmol, 0.02 equiv) were dissolved inCH₂Cl₂ (8.6 mL, 0.1 M) and 35% aqueous hydrogen peroxide (132 μL, 1.5mmol, 1.75 equiv) was added. Addition of the catalyst in a singleportion resulted in rapid over-oxidation, but addition in 3 portions, 20minutes apart resulted in clean conversion. The solution was stirred at750 rpm for 20 min, at which point a second portion of MTO (4.3 mg,0.017 mmol, 0.02 equiv) was added. After 20 min, a third and finalportion of MTO (4.3 mg, 0.017 mmol, 0.02 equiv) was added. After afurther 20 min (for a total of 1 h), LCMS showed complete conversion tothe bis-N-oxide, so the reaction was diluted with 8.6 mL 1M HCl and 17mL methanol was added to achieve phase mixing. After 16 h, LCMS showedcomplete conversion to the free alcohol. Any remaining oxidant wasquenched with aqueous sodium thiosulfate, the layers were separated, andthe aqueous phase was extracted with CH₂Cl₂ until no yellow colorpersisted. The combined organic phases were concentrated in vacuo anddried azeotropically with benzene, providing the analytically purebis-N-oxide. bis-N-oxide 19 was not stable to Na₂SO₄, MgSO₄, or SiO₂,and as such it was neither dried nor purified by column chromatography.Yellow solid, 368 mg, 0.765 mmol, 89% yield. ¹H NMR (500 MHz, CDCl₃) δ8.19 (s, 1H), 7.91 (s, 1H), 7.58 (s, 1H), 6.71 (s, 1H), 5.09 (d, J=14.4Hz, 1H), 4.87 (d, J=14.4 Hz, 1H), 4.05 (s, 3H), 4.03 (s, 3H), 3.94 (s,3H), 3.80 (s, 3H), 3.47 (s, 3H), 2.51 (s, 3H), 2.30 (s, 3H); 160.7,154.2, 154.1, 150.0, 143.9, 141.8, 138.3, 135.5, 129.9, 128.7, 128.5,126.0, 126.0, 125.0, 123.8, 122.1, 118.8, 98.4, 62.3, 61.5, 61.2, 60.7,56.4, 17.4, 17.0, 10.2; IR (thin film, NaCl): 3227.3, 2949.2, 2854.4,1607.8, 1456.6, 1332.2, 1235.5, 1113.3, 1001.4, 896.5, 816.4, 728.6;HRMS (ESI-TOF) calc'd for [M⁺] C₂₆H₂₈N₂O₇=480.1897, found 480.1902.

Example 6: Synthesis of Compound 6

(6S,9R,14aS,15R)-9-(hydroxymethyl)-2,4,10,11-tetramethoxy-3,12-dimethyl-5,6,9,14,14a,15-hexahydro-711-6,15-epiminobenzo[4,5]azocino[1,2-b]isoquinolin-7-one(6)

bis-Isoquinoline 22 (620 mg, 1.07 mmol, 1 equiv) was weighed in air intoa 100 mL roundbottom flask with a teflon-coated stir bar and the flaskwas brought into a nitrogen-filled glovebox. Tetra-n-butylammoniumiodide (238 mg, 0.644 mmol, 0.6 equiv, 3 equiv relative to Ir) was addedto the flask. and this solution was added to the bis-isoquinolineslurry, resulting in a yellow solution of protonated 22. was suspendedin 20 mL PhMe (22 is not fully soluble in PhMe alone). [Ir(cod)Cl]2(72.1 mg, 0.107 mmol, 0.1 equiv, 20 mol % Ir) and BTFM-Xyliphos (a.k.a.SL-J008-2, 205 mg, 0.225 mmol, 0.21 equiv) were dissolved in 10 mL PhMein a scintillation vial and the resulting solution was allowed to standfor 10 min. 38.3 mL of toluene was added to the flask containingbis-isoquinoline 22, followed by the addition of 5.4 mL AcOH, resultingin a yellow solution of protonated 22. The iridium-ligand solution wasthen added to the flask with two 5 mL rinses, bringing the final volumeto 53.7 mL of 9:1 PhMe:AcOH (0.02 M in 22). The flask was sealed with arubber septum that was then pierced with three 16 gauge (purple)needles, each bent at a 90° angle. The flask was placed inside apressure bomb, which was then sealed prior to removal from the gloveboxvia the large antechamber. At this stage, the tape was removed from thetop of the bomb and the pressure gauge was quickly screwed in place andtightened. With 200 rpm stirring, the bomb was charged to 10 bar of H2and slowly released. This process was repeated twice, before chargingthe bomb to 60 bar of H2, at which time it was placed in a preheated 60°C. oil bath. The bath was maintained at this temperature for 18 h, thenraised to 80° C. for 24 h. At this time, the bomb was removed from theoil bath and the hydrogen pressure was vented. The flask was removedfrom the bomb and the solution was transferred to a 250 mL roundbottomflask and basified by the careful addition of saturated aqueous K₂CO₃and water until pH>7. The solution was transferred to a separatoryfunnel and the layers were separated. The aqueous phase was extracted 5×with EtOAc, and the combined organic phases were washed twice with waterand once with brine, dried over Na₂SO₄, and concentrated. The productwas purified by column chromatography (15×1″, 1% MeOH/DCM+1% NEt₃). Atthis stage, ¹H NMR determined the purity of the product to be 90% as abrown foam. 469 mg, 422 mg adjusted for purity, 0.899 mmol, 83% yield,87% ee. Enantiomeric excess was determined by chiral HPLC analysis [AD,20% IPA, 280 nm, 1.0 mL/min: t_(R)(minor)=21.6 min, t_(R)(minor)=26.9min]. The product could then be crystallized to analytical and opticalpurity (>99% ee) by dissolving the brown foam in acetonitrile andallowing the solution to slowly evaporate under a stream of N₂. Thecrystals were washed 3× with 500 μL portions of −40° C. acetonitrile.The resulting crystals were dried in vacuo, providing 203 mg ofenantiopure (>99% ee) bis-tetrahydroisoquinoline 6. The mother liquorcould be purified by preparative SFC (AD-H, 20% IPA/CO₂, flow rate=40mL/min, t_(R)(minor)=25.0 min, t_(R)(major)=30 min) to provide theremaining material in enantiopure fashion. The crystals isolated abovewere used to collect the following characterization data. ¹H NMR (500MHz, CDCl₃) δ 6.73 (s, 1H), 6.35 (s, 1H), 5.79 (dd, J=6.7, 3.8 Hz, 1H),4.12-4.10 (m, 2H), 3.93 (dt, J=12.7, 2.9 Hz, 1H), 3.91 (s, 3H), 3.83 (s,3H), 3.78 (s, 3H), 3.70 (s, 3H), 3.43 (d, J=10.6 Hz, 1H), 3.22-3.10 (m,3H), 3.03 (dd, J=17.2, 6.6 Hz, 1H), 2.74 (dd, J=14.5, 2.6 Hz, 1H),2.67-2.60 (m, 1H), 2.25 (s, 3H), 2.15 (s, 3H); ¹³C NMR (126 MHz, CDCl₃)δ 172.9, 157.7, 156.6, 150.0, 149.7, 131.8, 131.2, 130.9, 125.0, 124.4,119.8, 119.7, 106.1, 69.0, 61.7, 60.7, 60.4, 60.0, 55.9, 55.0, 54.4,52.8, 33.2, 30.1, 15.9, 9.2; IR (thin film, NaCl): 3301.7, 3052.7,2940.2, 2859.4, 2835.6, 1621.9, 1614.0, 1486.0, 1463.1, 1455.0, 1410.0,1352.8, 1324.3, 1273.8, 1233.6, 1190.8, 1124.8, 1082.0, 1000.5, 957.7,925.7, 894.4, 849.2, 816.5, 788.5, 734.8, 703.2; HRMS (ESI-TOF) calc'dfor [M⁺] C₂₆H₃₂N₂O₆=468.2260, found 468.2255; [α]_(D)=−56.9° (c=0.5,CHCl₃).

Example 7: Synthesis of Compound 28

(6S,9R,14aS,15R)-9-(hydroxymethyl)-2,4,10,11-tetramethoxy-3,12,16-trimethyl-5,6,9,14,14a,15-hexahydro-711-6,15-epiminobenzo[4,5]azocino[1,2-b]isoquinolin-7-one(S6)

Enantiopure bis-tetrahydroisoquinoline 6 (125 mg, 0.267 mmol, 1 equiv)was dissolved in 1,2-dichloroethane (1,2-DCE, 5.3 mL, 0.05 M) and 37%aqueous formaldehyde (100 μL, 1.33 mmol, 5 equiv) was added. Thesolution was stirred at 800 rpm for 10 min, before sodiumtriacetoxyborohydride (565 mg, 2.67 mmol, 10 equiv) was added. Thissolution was stirred at 23° C. for 30 min, at which time LCMS showedfull conversion to the product. Citric acid monohydrate (840 mg, 4.00mmol, 15 equiv) was added to the solution, followed by 20 mL water. Thissolution was stirred for 10 min before the slow addition of saturatedaqueous K₂CO₃ until pH>7. The layers were separated and the aqueousphase was extracted with CH₂Cl₂. The combined organic phases were washedwith brine, dried over Na₂SO₄ and concentrated. The product was purifiedby column chromatography (1% MeOH/DCM+1% NEt₃). Colorless solid, 118.5mg, 0.246 mmol, 92% yield. ¹H NMR (500 MHz, CDCl₃) δ 6.72 (s, 1H), 6.34(s, 1H), 5.77 (dd, J=6.5, 3.8 Hz, 1H), 4.00 (dt, J=12.4, 3.0 Hz, 1H),3.90 (s, 3H), 3.83 (s, 3H), 3.80-3.76 (m, 2H), 3.78 (s, 3H), 3.70 (s,3H), 3.44 (ddd, J=8.6, 7.1, 6.0 Hz, 1H), 3.22-3.15 (m, 2H), 3.14 (dd,J=17.6, 6.5 Hz, 1H), 2.96 (br s, 1H), 2.94 (dd, J=17.6, 1.2 Hz, 1H),2.67 (dd, J=14.5, 2.6 Hz, 1H), 2.62-2.53 (m, 1H), 2.47 (s, 3H), 2.24 (s,3H), 2.15 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 173.4, 157.4, 156.7,150.0, 149.7, 131.7, 131.5, 128.8, 125.0, 124.4, 119.7, 119.0, 106.9,69.1, 61.4, 60.7, 60.4, 60.3, 60.0, 58.4, 55.9, 52.8, 46.1, 40.1, 33.0,24.2, 15.9; IR (thin film, NaCl): 3382.5, 2938.3, 2862.0, 1633.4,1608.1, 1485.1, 1462.9, 1445.8, 1410.0, 1359.5, 1325.2, 1271.9, 1232.7,1189.7, 1123.5, 1080.0, 1015.0, 1001.3, 962.6, 910.0, 847.7, 803.5,646.4; HRMS (ESI-TOF) calc'd for [M⁺] C₂₇H₃₄N₂O₆=482.2417, found482.2414; [α]_(D)=−76.2° (c=0.5, CHCl₃).

(6S,9R,14aS,15R)-1,13-dichloro-9-(hydroxymethyl)-2,4,10,11-tetramethoxy-3,12,16-trimethyl-5,6,9,14,14a,15-hexahydro-7H-6,15-epiminobenzo[4,5]azocino[1,2-b]isoquinolin-7-one(28)

bis-Tetrahydroisoquinoline S11 (88.6 mg, 0.183 mmol, 1.00 equiv) wasdissolved in HFIP (8.2 mL, 0.02 M after complete addition) and thesolution was cooled to 0° C. N-Chlorosaccharine (87.7 mg, 0.403 mmol,2.20 equiv) was dissolved in 1 mL HFIP and this solution was added at aslow dropwise pace, allowing the orange color to dispel after eachaddition, and the resulting yellow solution was stirred at 0° C. An LCMSsample taken 5 min after complete addition showed completedichlorination, so the reaction was quenched by the addition ofsaturated aqueous Na₂S₂O₃. The resulting mixture was transferred to aseparatory funnel with and diluted with CH₂Cl₂, creating a triphasicsystem with HFIP on bottom, CH₂Cl₂ on the bottom, and the aqueous phaseon top. The bottom two phases were collected directly in a 250 mLroundbottom flask. The aqueous phase was basified with K₂CO₃ andextracted with CH₂Cl₂, draining the organic phase directly into theflask. Excess acetic acid (˜100 μL) was added and the solution wasconcentrated, removing excess acetic acid by azeotropic drying withtoluene, and the resulting foam was dried at <1 torr for 1 h. The crudeproduct was dissolved in CH₂Cl₂ and washed with dilute aqueous K₂CO₃ andthe layers were separated. The aqueous phase was extracted with CH₂Cl₂and the combined organic phases were dried over Na₂SO₄ and concentrated.The product was purified by column chromatography (1% MeOH/CH₂Cl₂+1%NEt₃). White solid, 69.0 mg, 0.125 mmol, 68% yield. ¹H NMR (500 MHz,CDCl₃) δ 5.85 (dd, J=7.2, 4.1 Hz, 1H), 4.47 (dd, J=3.7, 1.1 Hz, 1H),4.04 (ddd, J=12.8, 3.7, 2.6 Hz, 1H), 3.90 (s, 3H), 3.82 (dd, J=15.6, 2.6Hz, 1H), 3.82 (s, 3H), 3.78-3.76 (m, 1H), 3.77 (s, 3H), 3.72 (s, 3H),3.42 (dt, J=10.8, 4.8 Hz, 1H), 3.18 (dd, J=7.0, 4.8 Hz, 1H), 3.13 (dd,J=18.2, 6.7 Hz, 1H), 3.13-3.08 (m, 1H), 3.00 (dd, J=18.1, 1.3 Hz, 1H),2.45 (s, 3H), 2.31 (s, 3H), 2.27 (s, 3H), 2.17 (dd, J=15.6, 12.8 Hz,1H); 173.3, 156.1, 153.8, 150.4, 148.3, 130.7, 129.8, 128.0, 127.9,126.2, 125.6, 124.5, 123.9, 69.1, 60.9, 60.5, 60.4, 60.4, 59.5, 58.8,57.6, 52.1, 40.3, 29.5, 24.7, 13.8, 10.1; IR (thin film, NaCl): 3417.7,2939.6, 1643.6, 1633.8, 1462.1, 1454.8, 1403.6, 1360.5, 1329.7, 1272.2,1236.1, 1224.0, 1191.6, 1146.7, 1105.6, 1081.9, 1004.6, 951.2, 931.7,833.0, 793.8, 767.9, 736.2, 702.5; HRMS (ESI-TOF) calc'd for [M⁺]C₂₇H₃₂N₂O₆Cl₂=550.1637, found 550.1637; [α]_(D)=−119.0° (c=0.5, CHCl₃).

Example 8: Synthesis of Compound S13

(6S,9R,14aS,15R)-1,13-dihydroxy-9-(hydroxymethyl)-2,4,10,11-tetramethoxy-3,12,16-trimethyl-5,6,9,14,14a,15-hexahydro-7H-6,15-epiminobenzo[4,5]azocino[1,2-b]isoquinolin-7-one(S13)

In a nitrogen-filled glovebox,(2′-Amino-1,1′-biphenyl-2-yl)methanesulfonatopalladium(II) dimer(Buchwald's dimer, 33.5 mg, 0.0453 mmol, 0.500 equiv) and5-[di(1-adamantyl)phosphino]-1′,3′,5′-triphenyl-1′H-[1,4′]bipyrazole(AdBippyPhos, 120.2 mg, 0.181 mmol, 2.00 equiv) were weighed into ascintillation vial and dioxane (8.1 mL) was added. The vial was sealedwith electrical tape and removed from the glovebox, sonicated briefly,and returned to the glovebox. The resulting tan solution was thentransferred to a 20 mL microwave vial containingbis-tetrahydroisoquinoline 28 (50.0 mg, 0.0907 mmol, 1.00 equiv) andCsOH.H₂O (152.3 mg, 0.907 mmol, 10.0 equiv), followed by a 1 mL rinse(9.1 mL total volume, 0.01 M in 28). The vial was sealed, removed fromthe glovebox, and placed in a preheated 90° C. oil bath. After 3 h, thevial was removed and allowed to cool fully to room temperature prior toremoving the seal. If the reaction vessel is prematurely exposed to airat elevated tempearture, aerobic oxidation leads to the formation ofquinones, which undergo hydrolysis of the vinylogous ester in thepresence of CsOH. The solution must be fully cooled to room temperatureprior to breaking the seal. The bisphenol product is not sensitive toaerobic oxidation, in the solid state or in solution. Acetic acid (46.5μL, 0.813 mmol, 9 equiv) was added to quench remaining CsOH and thecontents of the vial were transferred to a roundbottom flask, to whichsilica gel was added directly to dry load onto a silica gel column. Thesolution was concentrated, and the product was purified by columnchromatography (2-4-6-8-10% MeOH+CH₂Cl₂: 200 mL portions, no NEt₃ added,product elutes in the 6% portion). Tan solid, 17.2 mg, 0.0334 mmol, 37%yield. ¹H NMR (500 MHz, CDCl₃) δ 5.80 (dd, J=7.2, 4.2 Hz, 1H), 4.34 (d,J=2.0 Hz, 1H), 3.96 (dt, J=12.3, 2.5 Hz, 1H), 3.81 (s, 3H), 3.80 (dd,J=6.0, 1.0 Hz, 1H), 3.77 (s, 3H), 3.75 (s, 3H), 3.65 (s, 3H), 3.52 (brs, 1H), 3.46 (dd, J=15.7, 2.6 Hz, 1H), 3.42 (dd, J=11.0, 4.5 Hz, 1H),3.23 (dd, J=10.8, 7.2 Hz, 1H), 3.14 (dd, J=18.1, 6.7 Hz, 1H), 3.02 (d,J=18.0 Hz, 1H), 2.45 (s, 3H), 2.21 (s, 3H), 2.14 (s, 3H), 2.09 (dd,J=15.2, 12.2 Hz, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 173.6, 150.0, 149.7,146.8, 144.1, 143.5, 143.4, 124.6, 123.7, 122.6, 118.6, 118.3, 115.9,69.2, 61.0, 60.9, 60.4, 60.3, 59.6, 59.0, 55.3, 52.5, 40.1, 25.2, 24.5,9.7, 9.3, 1.2; IR (thin film, NaCl): 3332.3, 2937.3, 1613.3, 1462.2,1453.3, 1413.6, 1353.2, 1302.2, 1191.4, 1108.8, 1068.0, 1005.9, 910.3,836.1, 806.3, 730.6; HRMS (ESI-TOF) calc'd for [M⁺] C₂₇H₃₄N₂O₈=514.2315,found 514.2311; [α]_(D)=91.6° (c=0.5, CHCl₃).

Example 9: Synthesis of Compound S14

6S,7R,9R,14aS,15R)-1,13-dihydroxy-9-(hydroxymethyl)-2,4,10,11-tetramethoxy-3,12,16-trimethyl-6,7,9,14,14a,15-hexahydro-5H-6,15-epiminobenzo[4,5]azocino[1,2-b]isoquinoline-7-carbonitrile(S14)

In an oven-dried vial, LiAlH₄ solution (1.0 M in THF, 2 mL, 2.0 mmol)was cooled to 0° C. A solution of ethyl acetate (230 μL, 2.35 mmol) in 2mL THF was added slowly, and the resulting solution was stirred 30 minat 0° C., providing a 0.47 M solution of Li(EtO)₂AlH2 in THF.bis-Tetrahydroisoquinoline S13 (49.0 mg, 0.095 mmol, 1.0 equiv) wasdissolved in THF (4.8 mL, 0.02 M) and the resulting solution was cooledto 0° C. A solution of Li(EtO)₂AlH2 (0.47 M in THF, 3.0 mL, 1.43 mmol,15.0 equiv) was added slowly, resulting in extensive evolution of H2.After stirring 45 min, the reaction was quenched with acetic acid (115μL, 2.00 mmol, 21 equiv) and aqueous potassium cyanide (4.8 M, 120 μL,0.571 mmol, 6.0 equiv) was added, followed by celite and anhydrousNa₂SO₄ (roughly 1 g each). The solution was diluted with 8 mL THF andstirred 10 h, warming to room temperature. More celite was added, andthe suspension was filtered through celite, rinsing with EtOAc. Thefiltrate was transferred to a roundbottom flask and was concentrated. Atthis stage, LCMS revealed a ˜4:1 mixture of product S14 and startingmaterial S13, so the crude mixture was resubjected to the reductionconditions, using 3 mL THF as the reaction solvent and 1 mL of freshlyprepared Li(EtO)₂AlH₂ solution. After 10 min, LCMS showed very littleconversion of the remaining starting material, with some over-reducedproduct (m/z=501). The reaction mixture was quenched and worked up asdescribed above. The product was purified by column chromatography(50-75-100% EtOAc/hex, 200 mL each; product elutes in the 75% portion).Colorless solid, 25.2 mg, 0.0479 mmol, 50% yield ¹H NMR (400 MHz, CDCl₃)δ 4.19 (dD, J=2.7, 1.1 Hz, 1H), 4.00-4.05 (m, 2H), 3.81 (s, 3H), 3.751(s, 3H), 3.749 (s, 3H), 3.70 (s, 3H), 3.56 (dd, J=10.9, 4.4 Hz, 1H),3.40 (ddd, J=7.5, 2.5, 1.2 Hz, 1H), 3.31 (dt, J=12.1, 2.7 Hz, 1H), 3.18(d, J=9.4 Hz, 1H), 3.13 (dd, J=15.6, 2.7 Hz, 1H), 3.10 (dd, J=18.6, 7.8Hz, 1H), 2.51 (d, J=18.6 Hz, 1H), 2.34 (s, 3H), 2.22 (s, 3H), 2.09 (s,3H), 1.85 (dd, J=15.6, 12.0 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ 149.6,148.7, 146.6, 143.7, 143.4, 143.1, 125.4, 123.5, 122.7, 118.1, 118.0,117.1, 116.7, 66.2, 61.2, 61.0, 60.8, 60.4, 60.2, 58.5, 57.1, 56.7,55.2, 41.9, 25.4, 21.7, 9.8, 9.0; IR (thin film, NaCl): 3427.6, 2936.1,2832.7, 2228.1, 1606.8, 1463.2, 1412.1, 1384.5, 1349.9, 1319.9, 1300.9,1251.3, 1218.1, 1191.3, 1150.7, 1107.7, 1070.1, 1001.7, 981.7, 907.7,875.4, 829.8, 754.4; FIRMS (ESI-TOF) calc'd for [M⁺]C₂₈H₃₅N₃O₇=525.2475, found 525.2471; [α]_(D)=+22.9° (c=0.5, CHCl₃).

Example 10: Synthesis of (−)-Jorunnamycin A (S15)

bis-Tetrahydroisoquinoline S14 (22.0 mg, 41.9 μmol, 1.0 equiv) and4,5-dichloro-3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile (DDQ, 38.0mg, 167 μmol, 4.0 equiv) were weighed into a roundbottom flask and 8.4mL of a 9:1 mixture of acetone and water was added (0.005 M). The purplesolution gradually turned blood red. After 1 h, the reaction wasquenched with saturated aqueous NaHCO₃. The phases were separated andthe aqueous phase was extracted with ethyl acetate. The combined organicphases were washed with brine, dried over Na₂SO₄ and concentrated. Theproduct was purified using reverse phase (C₁₈) preparative HPLC(MeCN/0.4% acetic acid in water, 5.0 mL/min, monitor wavelength=254 nm,20-70% MeCN over 5 min, hold at 70% for 3 min, hold at 95% for 2 min.Product has t_(R)=7.2 min). Yellow film, 6.6 mg, 13.4 μmol, 32% yield.¹H NMR (500 MHz, CDCl₃) δ 4.11 (d, J=2.6 Hz, 1H), 4.08 (dd, J=3.0, 1.0Hz, 1H), 4.03 (s, 3H), 3.99 (s, 3H), 3.90 (q, J=3.1 Hz, 1H), 3.71 (dd,J=11.3, 3.4 Hz, 1H), 3.50 (s, 1H), 3.42 (ddd, J=7.4, 2.6, 1.5 Hz, 1H),3.18 (dt, J=11.4, 2.9 Hz, 1H), 2.93 (ddd, J=17.4, 2.8, 0.9 Hz, 1H), 2.83(dd, J=21.0, 7.5 Hz, 1H), 2.31 (s, 3H), 2.26 (d, J=21.0 Hz, 1H), 1.95(s, 3H), 1.94 (s, 3H), 1.41 (ddd, J=17.5, 11.5, 2.7 Hz, 1H); IR (thinfilm, NaCl): 3508.5, 2943.0, 2226.8, 1651.8, 1620.8, 1447.2, 1373.6,1310.6, 1277.4, 1236.0, 1190.6, 1151.1, 1098.1, 1077.8, 963.7, 886.8,775.3; HRMS (ESI-TOF) calc'd for [M⁺] C₂₈H₂₇N₃O₇=493.1849, found493.1848; [α]_(D)=−94.3° (c=0.35, CHCl₃).

Example 11: Synthesis of (−)-Jorumycin (1)

In a 1-dram vial, Jorunnamycin A (S15, 6.6 mg, 13.4 μmol, 1.0 equiv) and4-dimethylaminopyridine (DMAP, 4.9 mg, 40.1 μmol, 3.0 equiv) weredissolved in acetonitrile (400 μL, 0.03 M) and acetic anhydride (3.8 μL,40.1 μmol, 3.0 equiv) was added neat. The brown solution immediatelyturned yellow. After 30 minutes, LCMS showed complete conversion to theacetylated intermediate. At this stage, silver nitrate (57.0 mg, 334μmol, 25.0 equiv) and water (260 μL) were added in rapid succession. Thevial was resealed and placed in a preheated 45° C. heating block, thenprotected from light with aluminum foil. After 30 minutes, LCMS showedcomplete conversion to (−)-jorumycin (1), so the solution was filteredto remove AgCN and silver black, and the crude reaction mixture waspurified directly using preparative HPLC (MeCN/0.4% acetic acid inwater, 5.0 mL/min, monitor wavelength=265 nm, 10-55% MeCN over 7 min,ramp to 95% MeCN over 0.2 min, hold at 95% for 1.8 min for a total runtime of 9 min. Product has t_(R)=6.6 min). Yellow film, 4.8 mg, 9.12μmol, 68% yield. ¹H NMR (500 MHz, CDCl₃) δ 4.44 (dd, J=11.2, 3.5 Hz,1H), 4.44 (br s, 1H), 4.37 (d, J=3.1 Hz, 1H), 4.01 (s, 3H), 3.99 (s,3H), 3.92 (br s, 1H), 3.82 (dd, J=11.3, 3.4 Hz, 1H), 3.21-3.16 (m, 1H),3.14 (dd, J=7.3, 4.7 Hz, 1H), 2.84 (dd, J=16.6, 2.4 Hz, 1H), 2.66 (dd,J=21.1, 7.6 Hz, 1H), 2.27 (s, 3H), 2.23 (d, J=21.0 Hz, 1H), 1.96 (s,3H), 1.94 (s, 3H), 1.76 (s, 3H), 1.24 (ddd, J=16.6, 11.3, 2.6 Hz, 1H);¹³C NMR (126 MHz, CDCl₃) δ 186.0, 181.4, 170.2, 155.8, 155.4, 142.1,142.0, 137.4, 128.9, 128.5, 83.1, 64.4, 61.19, 61.17, 57.6, 54.4, 52.9,51.1, 41.6, 25.7, 20.74, 20.69, 8.9, 8.8; IR (thin film, NaCl): 3478.3,2923.5, 2850.7, 1738.4, 1651.6, 1620.8, 1449.0, 1373.6, 1309.4, 1260.4,1233.9, 1188.7, 1149.6, 1096.2, 1083.0, 1013.2, 901.9, 871.7, 839.6,801.2, 730.2; HRMS (ESI-TOF) calc'd for [M⁺] C₂₇H₃₀N₂O₉=526.1951, found526.1956.

Example 12: Monoisoquinoline Hydrogenation

N-benzoyl-(1R,3S)-1-(hydroxymethyl)-3-phenyl-1,2,3,4-tetrahydroisoquinoline(S17)

bis-Isoquinoline S16 (85 mg, 0.36 mmol, 1 equiv) was weighed in air intoa 100 mL roundbottom flask with a teflon-coated stir bar and the flaskwas brought into a nitrogen-filled glovebox. Tetra-n-butylammoniumiodide (19.9 mg, 0.054 mmol, 0.15 equiv, 3 equiv relative to Ir) wasadded to the flask. [Ir(cod)Cl]2 (6.0 mg, 0.009 mmol, 0.025 equiv, 5 mol% Ir) and BTFM-Xyliphos (SL-J008-2, 19.7 mg, 0.0216 mmol, 0.06 equiv)were dissolved in 6.2 mL PhMe in a scintillation vial and the resultingsolution was allowed to stand for 10 min. 10.2 mL of toluene was addedto the flask containing bis-isoquinoline S16 and TBAI, followed by theaddition of 5.4 mL AcOH, resulting in a yellow solution of protonatedS16. The iridium-ligand solution was then added to the flask (0.02 M inS16). The flask was sealed with a rubber septum that was then piercedwith three 16 gauge (purple) needles, each bent at a 90° angle. Theflask was placed inside the bomb, which was then sealed prior to removalfrom the glovebox via the large antechamber. At this stage, the tape wasremoved from the top of the bomb and the pressure gauge was quicklyscrewed in place and tightened. With 200 rpm stirring, the bomb wascharged to 10 bar of H2 and slowly released. This process was repeatedtwice, before charging the bomb to 60 bar of H₂, at which time it wasplaced in a preheated 60° C. oil bath. The bath was maintained at thistemperature for 18 h, then raised to 80° C. for 24 h. At this time, thebomb was removed from the oil bath and the hydrogen pressure was vented.The flask was removed from the bomb and the solution was transferred toa 250 mL roundbottom flask and basified by the careful addition ofsaturated aqueous K₂CO₃ and water until pH>7. The solution wastransferred to a separatory funnel and the layers were separated. Theaqueous phase was extracted 5× with EtOAc, and the combined organicphases were washed twice with water and once with brine, dried overNa₂SO₄, and concentrated. The crude tetrahydroisoquinoline was dissolvedin 3 mL THF and triethylamine (3 equiv), DMAP (0.1 equiv), and benzoylchloride (3 equiv) were added. The solution was stirred at 23° C. for 45min. Methanol (1 mL) and water (1 mL) were then added, followed bylithium hydroxide monohydrate (10 equiv). The solution was stirred 1 hat 23° C., at which time the solution was diluted with saturated aqueousNaHCO₃. The layers were separated and the aqueous layer was extractedwith EtOAc. The combined organic phases were washed with brine, driedwith Na₂SO₄, and concentrated. The product was purified by columnchromatography (1% MeOH in DCM). Colorless solid, 101.4 mg, 0.30 mmol,82% yield, 85% ee. Enantiomeric excess was determined by chiral SFCanalysis [AD, 20% IPA, 254 nm, 3.0 mL/min: t_(R)(minor)=3.78 min,t_(R)(minor)=5.15 min]. ¹H NMR (500 MHz, CDCl₃) δ 7.53-7.51 (m, 2H),7.42-7.38 (m, 2H), 7.36-7.27 (m, 5H), 7.25-7.19 (m, 2H), 7.08-7.05 (m,1H), 5.51-5.48 (m, 1H), 4.76 (td, J=2.0, 0.9 Hz, 1H), 4.25-4.21 (m, 1H),4.04-4.01 (m, 1H), 3.59 (ddd, J=14.7, 3.6, 0.9 Hz, 1H), 2.95-2.89 (m,2H); ¹H NMR (500 MHz, CDCl₃) δ 169.3, 140.0, 136.8, 135.8, 132.9, 131.5,128.5, 128.2, 128.2, 128.1, 127.8, 127.7, 126.9, 126.0, 123.6, 63.3,61.7, 59.7, 37.4; HRMS (ESI-TOF) calc'd for [M⁺] C₂₃H₂₁NO₂=344.1645,found 344.1646.

Example 13: Synthesis of BTFM-Xyliphos (27)

(S)-1-((R_(P))-2-bis(3,5-bis(trifluoromethyl)phenyl)phosphinoferrocen-1-yl)-1-dimethylamino-ethane(S7).

In a flame-dried 2-neck roundbottom flask equipped with a refluxcondenser, OH-ferrocenyldimethylaminoethane (S6) (2.18 g, 8.46 mmol, 1equiv) was dissolved in diethyl ether (85 mL, 0.1 M) and the solutionwas cooled to −78° C. t-Butyllithium in pentane (1.81 M, 5.85 mL, 10.6mmol, 1.25 equiv) was added at a dropwise pace over 20 min, causing theyellow solution to turn orange. The solution was stirred 10 min at −78°C., then removed from its bath and stirred for 1.5 h at 23° C., turningred. A solution of bis(3,5-bistrifluoromethylphenyl)chloro-phosphane[(BTFM)₂PCl, 5.0 g, 10.1 mmol, 1.2 equiv) dissolved in 5 mL diethylether was added at a dropwise pace, followed by a 5 mL rinse. Thesolution quickly turned brown and eventually precipitated LiCl, and thesolution was heated to reflux. After 1 h LCMS showed full conversion toproduct, so the reaction was quenched by the addition of ice followed bysaturated aqueous NaHCO₃. The layers were separated and the aqueousphase was extracted once with diethyl ether. The combined organic phaseswere washed with brine, dried over Na₂SO₄ and concentrated. The productwas purified by column chromatography (10% EtOAc/hex+0.5% NEt₃) as themajor orange band. Dark orange oil, 5.46 g, 7.65 mmol, 90% yield. NMRspectra were identical to the previously reported compound.^(v 1)H NMR(300 MHz, CDCl₃) δ 7.97 (br s, 1H), 7.95 (br s, 1H), 7.91 (br s, 1H),7.75 (br s, 1H), 7.63 (br s, 1H), 7.61 (br s, 1H), 4.49 (q, J=2.2 Hz,1H), 4.36 (t, J=2.6 Hz, 1H), 4.13 (qd, J=6.8, 2.4 Hz, 1H), 4.02 (s, 5H),3.65 (dt, J=2.4, 1.1 Hz, 1H), 1.70 (s, 6H), 1.21 (d, J=6.7 Hz, 3H); ¹⁹FNMR (282 MHz, CDCl₃) δ −62.8, −62.9; ³¹P NMR (121 MHz, CDCl₃) δ −19.8.

Bis(3,5-dimethylphenyl)phosphine oxide (S9)

Magnesium turnings (5.10 g, 210 mmol, 6 equiv) were washed with hexanesand dried in a 120° C. oven for 1 h. The turnings were placed in a 500mL 3-neck roundbottom flask and flame dried under vacuum. Upon coolingto room temperature, a small amount of iodine (˜50 mg) was added to theflask, and the solids were suspended in THF (120 mL). The flask wasfitted with a reflux condenser, then vacuum purged/backfilled withnitrogen three times, and warmed to 50° C. in an oil bath. A vent needlewas added at the top of the reflux condenser to allow rapid gas releaseduring the initiation of Grignard formation. Neat3,5-dimethylbromobenzene (14.3 mL, 105 mmol, 3 equiv) was then added ata slow dropwise pace. Formation of the Grignard reagent was indicated bythe disappearance of the dark brown THF-iodine adduct, at which pointthe addition was halted until a controlled, gentle reflux was obtained,and the vent needle was removed. Dropwise addition of the bromide wasresumed so as to maintain a gentle reflux. After the addition wascomplete, the solution was stirred at 50° C. for 30 min, then removedfrom its bath and cooled to 0° C. in an ice/water bath. Diethylphosphite (4.5 mL, 35 mmol, 1 equiv) was added at a fast dropwise pace,and the solution was stirred at 0° C. for 1 h. At this time, the refluxcondenser was replaced with an addition funnel, and ice cold 6M HCl (40mL, prepared by mixing 20 g ice with 20 mL concentrated HCl) was addedat a slow dropwise pace. 300 mL water was added and the solution wasstirred vigorously for 1 h. The layers were separated and the aqueousphase was thrice extracted with EtOAc. The combined organic layers werewashed with brine, dried over Na₂SO₄ and concentrated. The product waspurified by column chromatography (1-3-5% MeOH/DCM). White solid, 7.58g, 29.3 mmol, 84% yield. NMR spectra were identical to the previouslyisolated compound.^(vi 1)H NMR (300 MHz, CDCl₃) δ 7.94 (d, J=477 Hz,1H), 7.32 (dt, J=1.5, 0.7 Hz, 2H), 7.28 (dt, J=1.6, 0.7 Hz, 2H), 7.17(tp, J=1.7, 0.8 Hz, 2H), 2.34 (p, J=0.6 Hz, 12H); ³¹P NMR (121 MHz,CDCl₃) δ 22.71.

Bis(3,5-dimethylphenyl)phosphane (S10)

The phosphine oxide was reduced using the procedure of Busacca etal.^(vii) Colorless oil. NMR spectra were identical to the previouslyisolated compound.⁴¹ ¹H NMR (300 MHz, C₆D₆) δ 7.23 (dh, J=1.8, 0.6 Hz,2H), 7.21 (dh, J=1.8, 0.6 Hz, 2H), 6.70 (dtq, J=1.8, 1.3, 0.7 Hz, 2H),5.32 (d, J=214.7 Hz, 1H), 2.02 (q, J=0.7 Hz, 12H); ³¹P NMR (121 MHz,C₆D₆) δ −39.9.

BTFM-Xyliphos (27)

The ligand was synthesized by adapting the procedure from Dorta et al.for the synthesis of Xyliphos.⁴¹ Orange solid. NMR spectra wereidentical to the previously isolated compound.⁶ ¹H NMR (300 MHz, C₆D₆) δ8.12 (dt, J=1.9, 0.6 Hz, 1H), 8.11-8.09 (m, 1H), 7.95 (dq, J=1.8, 0.6Hz, 1H), 7.93-7.91 (m, 1H), 7.70 (dh, J=1.5, 0.7 Hz, 1H), 7.61-7.58 (m,1H), 7.24 (dt, J=1.4, 0.7 Hz, 1H), 7.23-7.21 (m, 1H), 7.14 (dd, J=1.6,0.8 Hz, 1H), 7.11 (dd, J=1.6, 0.8 Hz, 1H), 6.83 (tq, J=1.6, 0.8 Hz, 1H),6.67 (dp, J=1.7, 0.8 Hz, 1H), 4.07 (dtd, J=9.8, 6.9, 2.8 Hz, 1H), 3.97(tt, J=2.6, 0.6 Hz, 1H), 3.83-3.74 (m, 1H), 3.80-3.71 (m, 1H), 3.60 (s,5H), 2.17 (q, J=0.6 Hz, 6H), 2.05 (d, J=0.7 Hz, 6H), 1.50 (dd, J=6.8,5.4 Hz, 3H); ¹³C NMR (101 MHz, C₆D₆) δ 144.1 (d, J=14.4 Hz), 142.5 (dd,J=16.7, 3.2 Hz), 138.2 (d, J=4.9 Hz), 137.5 (d, J=7.4 Hz), 137.1 (d,J=18.1 Hz), 135.2 (d, J=23.4 Hz), 134.3 (dd, J=21.5, 1.7 Hz), 133.4 (d,J=20.0 Hz), 132.8 (d, J=16.9 Hz), 132.1 (d, J=7.6 Hz), 131.9-131.7 (m),131.5 (d, J=4.7 Hz), 131.2 (d, J=4.9 Hz), 130.2, 129.8 (d, J=15.6 Hz),125.1 (d, J=24.1 Hz), 122.4 (d, J=24.2 Hz), 121.2 (dp, J=121, 3.6 Hz),100.5 (d, J=20.8 Hz), 100.2 (d, J=20.9 Hz), 71.4 (dd, J=9.0, 3.6 Hz),70.6 (d, J=4.3 Hz), 70.3 (d, J=4.5 Hz), 69.8, 30.5 (dd, J=19.8, 9.5 Hz),21.3 (d, J=10.7 Hz), 15.9 (d, J=1.1 Hz); ¹⁹F NMR (282 MHz, C₆D₆) δ−62.66 (d, J=1.6 Hz); ³¹P NMR (121 MHz, C₆D₆) δ 11.62 (d, J=38.2 Hz),−22.86 (d, J=38.4 Hz).

REFERENCES

-   1. D. J. Newman, G. M. Cragg, J. Nat. Prod. 79, 629-661 (2016).-   2. J. D. Scott, R. M. Williams, Chem. Rev. 102, 1669-1730 (2002).-   3. M. Chrzanowska, M. D. Rozwadowska, Chem. Rev. 104, 3341-3370    (2004).-   4. M. Chrzanowska, A. Grajewska, M. D. Rozwadowska, Chem. Rev. 116,    12369-12465 (2016).-   5. C. Cuevas, A. Francesch, Nat. Prod. Rep. 26, 322-337 (2009).-   6. C. Cuevas, et al., Org. Lett. 2, 2545-2548 (2000).-   7. E. J. Corey, D. Y Gin, R. S. Kania, J. Am. Chem. Soc. 118,    9202-9203 (1996).-   8. A. G. Myers, D. W. Kung, J. Am. Chem. Soc. 121, 10828-10829    (1999).-   9. C. M. Rath, et al., ACS Chem. Biol. 6, 1244-1256 (2011).-   10. L.-Q. Song, Y.-Y. Zhang, J.-Y. Pu, M.-C. Tang, C. Peng, G.-L.    Tang, Angew. Chem., Int. Ed. 56, DOI: 10.1002/anie.201704726-   11. E. J. Martinez, T. Owa, S. L. Schreiber, E. J. Corey, Proc.    Natl. Acad. Sci. USA 96, 3496-3501 (1999).-   12. A. G. Myers, A. T. Plowright, J. Am. Chem. Soc. 123, 5114-5115    (2001).-   13. A. G. Myers, B. A. Lanman, J. Am. Chem. Soc. 124, 12969-12971    (2002).-   14. E. M. Ocio, et al., Blood 113, 3781-3791 (2009).-   15. A. Fontana, P. Cavaliere, S. Wahidulla, C. G. Naik, G. Cimino,    Tetrahedron 56, 7305-7308 (2000).-   16. J. W. Lane, Y. Chen, R. M. Williams, J. Am. Chem. Soc. 127,    12684-12690 (2005).-   17. Y.-C. Wu, J. Zhu, Org. Lett. 11, 5558-5561 (2009).-   18. W. Liu, X. Liao, W. Dong, Z. Yan, N. Wang, Z. Liu, Tetrahedron    68, 2759-2764 (2012).-   19. R. Chen, H. Liu, X. Chen, J. Nat. Prod. 76, 1789-1795 (2013).-   20. N. Saito, C. Tanaka, Y.-i. Koizumi, K. Suwanborirux, S.    Amnuoypol, S. Pummangura, A. Kubo, Tetrahedron 60, 3873-3881 (2004).-   21. S. Xu et al., Eur. J. Org. Chem. 975-983 (2017).-   22. J. W. Lown, A. V. Joshua, J. S. Lee, Biochemistry 21, 419-428    (1982).-   23. J. J. Perez-Ruixo, et al., Clin. Pharmacokinet. 46, 867-884    (2007).-   24. U.S. Food and Drug Administration, Center for Drug Evaluation    and Research (2015). Retrieved from    https://www.fda.gov/aboutfda/centersoffice    s/officeofmedicalproductsandtobacco/cder/(Identification No.    207953Orig1s000, Pharmacology Reviews).-   25. J. R. Spencer, et al., Bioorg. Med. Chem. Lett. 16, 4884-4888    (2006).-   26. J. M. Reid, M. J. Kuffel, S. L. Ruben, J. J. Morales, K. L.    Rinehart, D. P. Squillace, M. M. Ames, Clin. Cancer. Res. 8,    2952-2962 (2002).-   27. H.-S. Yeom, S. Kim, S. Shin, Synlett 924-928 (2008).-   28. U. K. Tambar, B. M. Stoltz, J. Am. Chem. Soc. 127, 5340-5341    (2005).-   29. K. M. Allan, B. D. Hong, B. M. Stoltz, Org. Biomol. Chem. 7,    4960-4964 (2009).-   30. P. M. Tadross, C. D. Gilmore, P. Bugga, S. C. Virgil, B. M.    Stoltz, Org. Lett. 12, 1224-1227 (2010).-   31. L.-C. Campeau, D. J. Schipper, K. Fagnou, I Am. Chem. Soc. 130,    3266-3267 (2008).-   32. Y. Tan, F. Barrios-Landeros, J. F. Hartwig, I Am. Chem. Soc.    134, 3683-3686 (2012).-   33. V. Boekelheide, W. J. Linn, I Am. Chem. Soc. 76, 1286-1291    (1954).-   34. A. A. Tabolin, S. L. Ioffe, Chem. Rev. 114, 5426-5476 (2014).-   35. C. Copéret, H. Adolfsson, T.-A. V. Khuong, A. K. Yudin, K. B.    Sharpless, I Org. Chem. 63, 1740-1741 (1998).-   36. D.-S. Wang, Q.-A. Chen, S.-M. Lu, Y.-G. Zhou, Chem. Rev. 112,    2557-2590 (2012).-   37. S.-M. Lu, Y.-Q. Wang, X.-W. Han, Y.-G. Zhou, Angew. Chem., Int.    Ed. 45, 2260-2263 (2006).-   38. L. Shi, Z.-S. Ye, L.-L. Cao, R.-N. Guo, Y. Hu, Y.-G. Zhou,    Angew. Chem., Int. Ed. 51, 8286-8289 (2012).-   39. Y. Kita, K. Yamaji, K. Higashida, K. Sathaiah, A. Iimuro, K.    Mashima, Angew. Chem., Int. Ed. 52, 2046-2050 (2013).-   40. J. Wen, R. Tan, S. Liu, Q. Zhao, X. Zhang, Chem. Sci. 7,    3047-3051 (2016).-   41. R. Dorta, D. Broggini, R. Stoop, H. Rüegger, F. Spindler, A.    Togni, Chem. Eur. J. 10, 267-278 (2004).-   42. S,R_(P)-BTFM-Xyliphos (27) is produced and sold by Solvias AG    and is licensed to Sigma-Aldrich Co., and Strem Chemicals under the    name SL-J008-2. For a scalable synthesis of 27, see Supplementary    Materials.-   43. E. J. Martinez, E. J. Corey, Org. Lett. 2, 993-996 (2000).-   i. A. B. Pangborn, M. A. Giardello, R. H. Grubbs, R. K. Rosen, F. J.    Timmers, Organometallics, 15, 1518-1520 (1996).-   ii. D. L. Comins, J. D. Brown, J. Org. Chem. 49, 1078-1083 (1984).-   iii. M. Harmata, W. Yang, C. L. Barnes, Tetrahedron Lett. 50,    2326-2328 (2009).-   iv. K. C. Nicolau, D. Rhoades, M. Lamani, M. R. Pattanayak, S. M.    Kumar, J. Am. Chem. Soc. 138, 7532-7535 (2016).-   v. P. M. Tadross, C. D. Gilmore, P. Bugga, S. C. Virgil, B. M.    Stoltz, Org. Lett. 12, 1224-1227 (2010).-   vi. F. Spindler, Patent Number EP 0646590 A1.-   vii. M. Jin, M. Nakamura, Chem. Lett. 42, 1035-1037 (2013).-   viii C. A. Busacca, J. C. Lorenz, N. Grinberg, N. Haddad, M.    Hrapchak, B. Latli, H. Lee, P. Sabila, A. Saha, M. Sarvestani, S.    Shen, R. Varsolona, X. Wei, C. H. Senanayake, Org. Lett. 7,    4277-4280 (2005).

Incorporation by Reference

All publications and patents mentioned herein are hereby incorporated byreference in their entirety as if each individual publication or patentwas specifically and individually indicated to be incorporated byreference. In case of conflict, the present application, including anydefinitions herein, will control.

EQUIVALENTS

While specific embodiments of the subject invention have been discussed,the above specification is illustrative and not restrictive. Manyvariations of the invention will become apparent to those skilled in theart upon review of this specification and the claims below. The fullscope of the invention should be determined by reference to the claims,along with their full scope of equivalents, and the specification, alongwith such variations.

We claim:
 1. A method of preparing a compound of Formula (II):

comprising combining a compound of Formula (III):

with a compound of Formula (IV):

and a transition metal catalyst under cross-coupling conditions,wherein, as valence and stability permit: R¹ and R⁷ are eachindependently hydrogen, hydroxyl, halogen, nitro, alkyl, alkenyl,alkynyl, cyano, carboxyl, sulfate, amino, alkoxy, alkylamino, alkylthio,ether, thioether, ester, amide, thioester, carbonate, carbamate, urea,sulfonate, sulfone, sulfoxide, sulfonamide, acyl, acyloxy,alkylsilyloxy, or acylamino; each instance of R², R³, R⁴, R⁵, R⁸, R⁹,R¹⁰, and R¹¹ is independently hydrogen, hydroxyl, halogen, nitro, alkyl,alkenyl, alkynyl, cyano, carboxyl, sulfate, amino, alkoxy, alkylamino,alkylthio, ether, thioether, ester, amide, thioester, carbonate,carbamate, urea, sulfonate, sulfone, sulfoxide, sulfonamide, acyl,acyloxy, alkylsilyloxy, acylamino, aryl, heteroaryl, carbocyclyl, orheterocyclyl; R⁶ is hydrogen, hydroxyl, halogen, nitro, alkyl, alkenyl,alkynyl, cyano, carboxyl, sulfate, amino, alkoxy, alkylamino, alkylthio,ether, thioether, ester, amide, thioester, carbonate, carbamate, urea,sulfonate, sulfone, sulfoxide, sulfonamide, acyl, acyloxy,alkylsilyloxy, or acylamino; or any two of R¹, R², R³, R⁴, R⁵, and R⁶,together with the carbon atoms to which they are attached, form an aryl,heteroaryl, carbocyclyl, or heterocyclyl; or any two of R⁷, R⁸, R⁹, R¹⁰,and R¹¹, together with the carbon atoms to which they are attached, forman aryl, heteroaryl, carbocyclyl, or heterocyclyl; and R¹³ and R¹⁴ areeach independently hydroxyl, nitro, cyano, carboxyl, sulfate, amino,alkoxy, alkylamino, alkylthio, ether, thioether, ester, amide,thioester, carbonate, carbamate, urea, sulfonate, sulfone, sulfoxide,sulfonamide, acyl, acyloxy, alkylsilyloxy, or acylamino.
 2. The methodof claim 1, wherein R¹³ and R¹⁴ are each independently unsubstitutedalkyl or alkyl substituted with one or more substituents selected fromhydroxy, alkoxy, acyloxy, amino and thio.
 3. The method of claim 1,wherein the transition metal catalyst comprises a nickel, palladium, orplatinum catalyst.
 4. The method of claim 3, wherein the transitionmetal catalyst comprises a palladium catalyst is-selected from Pd/C,Pd₂(DBA)₃, Pd(PPh₃)₄, Pd(OC(O)R^(c))₂, Pd(OAc)₂, PdCl₂, Pd(PhCN)₂Cl₂,Pd(CH₃CN)₂Cl₂, PdBr₂, Pd(acac)₂, [Pd(allyl)Cl]2, Pd(TFA)₂, Pd₂(pmdba)₃,Pd(P(t-Bu)₂Me)₂, and pre-formed Pd(II)-ligand complexes; wherein R^(C)is optionally substituted alkyl, alkenyl, alkynyl, aryl, heteroaryl,aralkyl, heteroaralkyl, cycloalkyl, heterocycloalkyl, (cycloalkyl)alkyl,or (heterocycloalkyl)alkyl.
 5. The method of claim 4, wherein thepalladium catalyst is Pd(P(t-Bu)₂Me)₂.
 6. The method of claim 3, whereinthe transition metal catalyst is used in an amount from about 0.5 mol %to about 50 mol % relative to the compound of formula (III) or (IV). 7.The method of claim 1, wherein R¹ is hydrogen.
 8. The method of claim 1,wherein R¹ is unsubstituted alkyl or alkyl substituted with one or moresubstituents selected from hydroxy, alkoxy, acyloxy, amino, and thio. 9.The method of claim 1, wherein R² is selected from H, halo and hydroxy.10. The method of claim 1, wherein R³ is alkyl.
 11. The method of claim1, wherein R⁴ is alkoxy.
 12. The method of claim 1, wherein R⁵ ishydroxy or alkoxy.
 13. The method of claim 1, wherein R⁶ isunsubstituted alkyl or alkyl substituted with one or more substituentsselected from hydroxy, alkoxy, acyloxy, amino and thio.
 14. The methodof claim 1, wherein R⁷ is unsubstituted alkyl or alkyl substituted withone or more substituents selected from hydroxy, alkoxy, acyloxy, amino,and thio.
 15. The method of claim 1, wherein R⁷ is H, halo or hydroxy.16. The method of claim 1, wherein R⁸ is alkoxy.
 17. The method of claim1, wherein R⁹ is alkyl.
 18. The method of claim 1, wherein R¹⁰ ishydroxy or alkoxy.
 19. The method of claim 1, wherein R¹¹ is H.
 20. Themethod of claim 1, wherein each instance of R², R³, R⁴, R⁵, R⁸, R⁹, R¹⁰,and R¹¹ is independently unsubstituted alkyl or alkyl substituted withone or more substituents selected from hydroxy, alkoxy, acyloxy, amino,and thio.